Article

Antiviral Activity of the Zinc Ionophores Pyrithione and Hinokitiol against Picornavirus Infections

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Abstract

We have discovered two metal ion binding compounds, pyrithione (PT) and hinokitiol (HK), that efficiently inhibit human rhinovirus, coxsackievirus, and mengovirus multiplication. Early stages of virus infection are unaffected by these compounds. However, the cleavage of the cellular eukaryotic translation initiation factor eIF4GI by the rhinoviral 2A protease was abolished in the presence of PT and HK. We further show that these compounds inhibit picornavirus replication by interfering with proper processing of the viral polyprotein. In addition, we provide evidence that these structurally unrelated compounds lead to a rapid import of extracellular zinc ions into cells. Imported Zn2+ was found to be localized in punctate structures, as well as in mitochondria. The observed elevated level of zinc ions was reversible when the compounds were removed. As the antiviral activity of these compounds requires the continuous presence of the zinc ionophore PT, HK, or pyrrolidine-dithiocarbamate, the requirement for zinc ions for the antiviral activity is further substantiated. Therefore, an increase in intracellular zinc levels provides the basis for a new antipicornavirus mechanism.

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... Thereby, it facilitates Zn's entry across a cell's lipid membrane and considerably increases Zn's intracellular levels, particularly in the endosomallysosomal section. 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. ...
... 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. 193 Several ongoing studies are utilizing various updated scientific approaches to accomplish a better understanding of antiviral pharmacodynamics. ...
... 130,140 • Some preliminary research identified Zn ionophore stimulates zinc's efficiency in its antiviral ability against COVID-19. 142,190,191 ...
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Nandeeta Samad,1 Temitayo Eniola Sodunke,2 Abdullahi Rabiu Abubakar,3 Iffat Jahan,4 Paras Sharma,5 Salequl Islam,6 Siddhartha Dutta,7 Mainul Haque8 1Department of Public Health, North South University, Dhaka, 1229, Bangladesh; 2Department of Anatomy, University of Ilorin, Ilorin, Kwara State, Nigeria; 3Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Bayero University, Kano, 700233, Nigeria; 4Department of Physiology, Eastern Medical College, Cumilla, Bangladesh; 5Department of Pharmacognosy, BVM College of Pharmacy, Gwalior, India; 6Department of Microbiology, Jahangirnagar University, Dhaka, 1342, Bangladesh; 7Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India; 8The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, MalaysiaCorrespondence: Mainul HaqueUnit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur, 57000, MalaysiaTel +60 10 926 5543Email runurono@gmail.comAbstract: The global pandemic from COVID-19 infection has generated significant public health concerns, both health-wise and economically. There is no specific pharmacological antiviral therapeutic option to date available for COVID-19 management. Also, there is an urgent need to discover effective medicines, prevention, and control methods because of the harsh death toll from this novel coronavirus infection. Acute respiratory tract infections, significantly lower respiratory tract infections, and pneumonia are the primary cause of millions of deaths worldwide. The role of micronutrients, including trace elements, boosted the human immune system and was well established. Several vitamins such as vitamin A, B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays essential physiological roles in promoting the immune system. Furthermore, zinc is an indispensable microelement essential for a thorough enzymatic physiological process. It also helps regulate gene-transcription such as DNA replication, RNA transcription, cell division, and cell activation in the human biological system. Subsequently, zinc, together with natural scavenger cells and neutrophils, are also involved in developing cells responsible for regulating nonspecific immunity. The modern food habit often promotes zinc deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the various roles played by zinc in the management of COVID-19 infection.Keywords: zinc therapy, microelement, immune-boosting, efficacy, COVID-19, viral infections, pneumonia, pandemic
... Zinc supplementation has been minimally studied in COVID-19; however, one trial demonstrates that zinc, "Экономика и социум" №2(93)-2 2022 www.iupr.ru 226 both alone and in combination with vitamin C, showed no significant decreases in COVID-19-related symptoms compared to no study intervention [49]. Zinc is crucial for normal development and functioning of cells mediating part of the immune system. ...
... More often than other drugs, plasma substitutes are administered by injection, dehydrating, anesthetic, radiopaque drugs, solutions of antibiotics (penicillins and cephalosporins), local anesthetics, antihistamines, steroidal and non-steroidal anti-inflammatory drugs [8,9,49,50,51,52]. The chosen route of administration of drugs in critically ill patients caused by severe concomitant trauma is especially relevant, as it allows you to quickly and effectively eliminate dangerous disorders of vital organs and systems [53]. ...
... 1-сонли БҲМС "Ҳисоб сиёсати ва молиявий ҳисобот"нинг 14-пункти молиявий ҳисобот таркибида тақдим этиладиган қўшимча ахборот нимадан иборат бўлишини тавсифлаб беради: "Турли хўжалик юритувчи субъектлар фаолиятининг кўп қирралилиги ҳисобга олинади, молиявий ҳисоботлар улардан фойдаланувчиларни иқтисодий қарорлар қабул қилиш учун зарур бўлган барча ахборот билан таъминлай олмайди, шу сабабли молиявий ҳисоботларга қўшимча равишда маъмурият томонидан тузиладиган молиявий шарҳ киритилади, унда хўжалик юритувчи субъект молиявий фаолияти ва молиявий ҳолатининг асосий белгилари тушунтириб берилади ва улар дуч келаётган ноаниқликлар баён қилинади. Бу шарҳда хўжалик юритувчи субъектнинг фаолияти натижаларига, фаолиятни қўллабқувватлаш ва мустаҳкамлаш учун инвестиция сиёсатига, жумладан жорий даврда, хусусан келгуси даврларда дивиденд сиёсатига таъсир этувчи асосий омиллар очиб берилади..." 49 Юқоридагилардан кўриниб турибдики, мамлакатимизда молиявийиқтисодий таҳлилнинг мунтазам олиб борилишини зарур қилиб қўювчи меъёрий-ҳуқуқий асослар амалда мавжуд. Лекин шу билан бирга, бу борадаги мавжуд қонунчилик ҳужжатларининг ишлаш механизмларини шакллантирилиши борасидаги ишлар давом эттирилиши лозим. ...
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The development of science and technology proves once again how infinite human needs are. The concentration of the population in large cities, on the one hand, accelerates the process of urbanization and affects the level of development of the state, on the other hand, the state of the environment has a negative impact on urban ecology. From ancient times the population has been striving to create favourable conditions for themselves, and such a process is still going on, especially when the negative consequences of this are clearly felt in the health of the population living in cities. Solving this problem is one of the main tasks of urboecology. The development of modern methods of geo-ecological monitoring of the ecological condition of cities, especially in areas with high industrial specialization, the development of measures to improve the health of the population in ecologically critical areas is of great importance today. To this end, this article discusses in detail the industrialized Navoi region and its urban and ecological situation, the factors affecting it.
... Thereby, it facilitates Zn's entry across a cell's lipid membrane and considerably increases Zn's intracellular levels, particularly in the endosomallysosomal section. 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. ...
... 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. 193 Several ongoing studies are utilizing various updated scientific approaches to accomplish a better understanding of antiviral pharmacodynamics. ...
... 130,140 • Some preliminary research identified Zn ionophore stimulates zinc's efficiency in its antiviral ability against COVID-19. 142,190,191 ...
Article
Full-text available
Abstract: The global pandemic from COVID-19 infection has generated significant public health concerns, both health-wise and economically. There is no specific pharmacological antiviral therapeutic option to date available for COVID-19 management. Also, there is an urgent need to discover effective medicines, prevention, and control methods because of the harsh death toll from this novel coronavirus infection. Acute respiratory tract infections, significantly lower respiratory tract infections, and pneumonia are the primary cause of millions of deaths worldwide. The role of micronutrients, including trace elements, boosted the human immune system and was well established. Several vitamins such as vitamin A, B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays essential physiological roles in promoting the immune system. Furthermore, zinc is an indispensable microelement essential for a thorough enzymatic physiological process. It also helps regulate gene-transcription such as DNA replication, RNA transcription, cell division, and cell activation in the human biological system. Subsequently, zinc, together with natural scavenger cells and neutrophils, are also involved in developing cells responsible for regulating nonspecific immunity. The modern food habit often promotes zinc deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the various roles played by zinc in the management of COVID-19 infection.
... Thereby, it facilitates Zn's entry across a cell's lipid membrane and considerably increases Zn's intracellular levels, particularly in the endosomallysosomal section. 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. ...
... 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. 193 Several ongoing studies are utilizing various updated scientific approaches to accomplish a better understanding of antiviral pharmacodynamics. ...
... 130,140 • Some preliminary research identified Zn ionophore stimulates zinc's efficiency in its antiviral ability against COVID-19. 142,190,191 ...
Article
Full-text available
Abstract: The global pandemic from COVID-19 infection has generated significant public health concerns, both health-wise and economically. There is no specific pharmacological antiviral therapeutic option to date available for COVID-19 management. Also, there is an urgent need to discover effective medicines, prevention, and control methods because of the harsh death toll from this novel coronavirus infection. Acute respiratory tract infections, significantly lower respiratory tract infections, and pneumonia are the primary cause of millions of deaths worldwide. The role of micronutrients, including trace elements, boosted the human immune system and was well established. Several vitamins such as vitamin A, B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays essential physiological roles in promoting the immune system. Furthermore, zinc is an indispensable microelement essential for a thorough enzymatic physiological process. It also helps regulate gene-transcription such as DNA replication, RNA transcription, cell division, and cell activation in the human biological system. Subsequently, zinc, together with natural scavenger cells and neutrophils, are also involved in developing cells responsible for regulating nonspecific immunity. The modern food habit often promotes zinc deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the various roles played by zinc in the management of COVID-19 infection.
... Thereby, it facilitates Zn's entry across a cell's lipid membrane and considerably increases Zn's intracellular levels, particularly in the endosomallysosomal section. 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. ...
... 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. 193 Several ongoing studies are utilizing various updated scientific approaches to accomplish a better understanding of antiviral pharmacodynamics. ...
... 130,140 • Some preliminary research identified Zn ionophore stimulates zinc's efficiency in its antiviral ability against COVID-19. 142,190,191 ...
... Direct antiviral effects of zinc were reported for respiratory syncytial virus, HIV, coronaviridae, picornaviridae (rhinovirus, coxsackievirus, cardio virus A, foot and mouth disease virus), HPV, equine arteritis virus (EAV), varicella-zoster virus, metapneumovirus, herpes simplex virus (HSV1 and HSV2), and HCV (110,137,210,241). Zinc supplementation was studied by adding zinc extracellularly to cultures of virus-infected cells or in clinical zinc supplementation studies. ...
... Moreover, the cleavage of large viral polypeptides into smaller peptides, which is necessary for the formation of the various viral proteins and thus new viral particles, was significantly inhibited by zinc (100 μM), as observed for various picornaviridae in vitro (136). In line with this finding, treatment with HK (45-125 μM) or pyrithione (5-10 μM) decreased the activity of rhinoviral 2A protease and subsequent cleavage of eIF4GI (eukaryotic translation initiation factor 4γ1), which is essential for initiation of translation as well as the proper processing of viral polyproteins (137). The zinc ionophores did not affect the vitality of the infected cells (137). ...
... In line with this finding, treatment with HK (45-125 μM) or pyrithione (5-10 μM) decreased the activity of rhinoviral 2A protease and subsequent cleavage of eIF4GI (eukaryotic translation initiation factor 4γ1), which is essential for initiation of translation as well as the proper processing of viral polyproteins (137). The zinc ionophores did not affect the vitality of the infected cells (137). In another study focusing on HSV, pyrithione treatment (10 μM) and thus increased intracellular zinc suppressed the expression of glycoprotein D and infected cell polypeptide 4. The involvement of those proteins in transcriptional activation of other viral genes explains the strong impact of zinc on viral replication. ...
Article
Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... This natural compound has shown numerous pharmacological properties, including antibacterial [6,7], antifungal [8], anti-inflammatory, anti-enzymatic [9,10], anticancer [11,12], antioxidant, neuroprotective [13], antidiabetic (Yamane), antiviral [14], antiplasmodial [15], and hepatoprotective effects [16]. Hinokitiol has demonstrated various anticancer activities against a wide variety of cell lines. ...
... It has been shown that viral replication is inhibited by hinokitiol by impairing viral polyprotein processing; however, this ability is determined by the availability of zinc ions. Thus, a rise in intracellular zinc levels provides the grounding for a new antipicornavirus mechanism [14]. ...
... Krenn et al. [14] demonstrated that a rapid import of extracellular zinc into the cytoplasm was caused by the metal ion binding compounds, such as hinokitiol. Basically, the human coxsackievirus, rhinovirus, and mengovirus multiplication were inhibited efficiently by hinokitiol treatment. ...
Article
Full-text available
Hinokitiol is a natural bioactive compound found in several aromatic and medicinal plants. It is a terpenoid synthetized and secreted by different species as secondary metabolites. This volatile compound was tested and explored for its different biological properties. In this review, we report the pharmacological properties of hinokitiol by focusing mainly on its anticancer mechanisms. Indeed, it can block cell transformation at different levels by its action on the cell cycle, apoptosis, autophagy via inhibiting gene expression and dysregulating cellular signaling pathways. Moreover, hinokitiol also exhibits other pharmacological properties, including antidiabetic, anti-inflammatory, and antimicrobial effects. It showed multiple and several effects through its inhibition, interaction and/or activation of the main cellular targets inducing these pathologies.
... Zinc ionophores (Table 1; Figure 2) have been shown to inhibit replication of various viruses in vitro, including coxsackievirus [63,65], equine arteritis virus [68], coronavirus [68], HCV [69], HSV [70], HCoV-229E [71], HIV [72,73], mengovirus [63,65], MERS-CoV [71], rhinovirus [65], SARS-CoV-1 [68], and Zika virus [74]. ...
... Zinc ionophores (Table 1; Figure 2) have been shown to inhibit replication of various viruses in vitro, including coxsackievirus [63,65], equine arteritis virus [68], coronavirus [68], HCV [69], HSV [70], HCoV-229E [71], HIV [72,73], mengovirus [63,65], MERS-CoV [71], rhinovirus [65], SARS-CoV-1 [68], and Zika virus [74]. ...
... Zinc ionophores (Table 1; Figure 2) have been shown to inhibit replication of various viruses in vitro, including coxsackievirus [63,65], equine arteritis virus [68], coronavirus [68], HCV [69], HSV [70], HCoV-229E [71], HIV [72,73], mengovirus [63,65], MERS-CoV [71], rhinovirus [65], SARS-CoV-1 [68], and Zika virus [74]. ...
Chapter
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Zinc is a trace metal ion that has a role in both physiological and pathological processes, making it one of the most common and necessary components involved in brain function. Besides, zinc is required for cell proliferation control in a variety of mechanisms, including hormonal regulation of cell division. Also, zinc serves as a biochemical signal to immune cells and transcription factors involved in the synthesis of inflammatory cytokines. On the other hand, zinc has a variety of crucial roles in neurogenesis and also acts as a neuromodulator on a wide range of membrane receptors, ion channels, and transporters. Zinc is produced by neurons under several conditions to activate microglia. The link between zinc dysregulation and psychiatric disorder was that zinc acts as an inhibitory modulator at the N-methyl-D aspartic acid (NMDA) glutamate receptor. Ionophores are ion carrier molecules that reversibly bind and transport ions through biological membranes. Ionophores can be natural or synthetic products. Zinc ionophores such as quercetin, epigallocatechin gallate (EGCG), hinokitol, and proanthocyanidins have been shown to protect brain health, particularly in depression clinically significant depression and depressive symptoms in post-COVID-19 syndrome may have severe implications as it relates to life outcomes quality, herein according to previous research studies, we showed zinc deficiency as a possible risk factor for depression symptoms, which were commonly observed following severe infection of COVID-19.
... Zinc supplementation has been minimally studied in COVID-19; however, one trial demonstrates that zinc, "Экономика и социум" №2(93)-2 2022 www.iupr.ru 226 both alone and in combination with vitamin C, showed no significant decreases in COVID-19-related symptoms compared to no study intervention [49]. Zinc is crucial for normal development and functioning of cells mediating part of the immune system. ...
... More often than other drugs, plasma substitutes are administered by injection, dehydrating, anesthetic, radiopaque drugs, solutions of antibiotics (penicillins and cephalosporins), local anesthetics, antihistamines, steroidal and non-steroidal anti-inflammatory drugs [8,9,49,50,51,52]. The chosen route of administration of drugs in critically ill patients caused by severe concomitant trauma is especially relevant, as it allows you to quickly and effectively eliminate dangerous disorders of vital organs and systems [53]. ...
... 1-сонли БҲМС "Ҳисоб сиёсати ва молиявий ҳисобот"нинг 14-пункти молиявий ҳисобот таркибида тақдим этиладиган қўшимча ахборот нимадан иборат бўлишини тавсифлаб беради: "Турли хўжалик юритувчи субъектлар фаолиятининг кўп қирралилиги ҳисобга олинади, молиявий ҳисоботлар улардан фойдаланувчиларни иқтисодий қарорлар қабул қилиш учун зарур бўлган барча ахборот билан таъминлай олмайди, шу сабабли молиявий ҳисоботларга қўшимча равишда маъмурият томонидан тузиладиган молиявий шарҳ киритилади, унда хўжалик юритувчи субъект молиявий фаолияти ва молиявий ҳолатининг асосий белгилари тушунтириб берилади ва улар дуч келаётган ноаниқликлар баён қилинади. Бу шарҳда хўжалик юритувчи субъектнинг фаолияти натижаларига, фаолиятни қўллабқувватлаш ва мустаҳкамлаш учун инвестиция сиёсатига, жумладан жорий даврда, хусусан келгуси даврларда дивиденд сиёсатига таъсир этувчи асосий омиллар очиб берилади..." 49 Юқоридагилардан кўриниб турибдики, мамлакатимизда молиявийиқтисодий таҳлилнинг мунтазам олиб борилишини зарур қилиб қўювчи меъёрий-ҳуқуқий асослар амалда мавжуд. Лекин шу билан бирга, бу борадаги мавжуд қонунчилик ҳужжатларининг ишлаш механизмларини шакллантирилиши борасидаги ишлар давом эттирилиши лозим. ...
... Earlier it was also shown that Zn 2+ inhibited the proteolytic processing of replicase polyproteins [66]. To allow Zn 2+ to exert its inhibitory effect on SARS-CoV-2 viral replication, Zn 2+ entry inside the cell might be enhanced by ionophores such as dithiocarbamates [67], pyrithione [65,68], zincophorin [69], and hydroxychloroquine [65,70,71]. It can be noted that a meta-analysis involving 19 reported studies suggested that chloroquine/hydroxychloroquine was associated with a reduced risk of CVD in patients with rheumatic diseases [72]. ...
... The ability of Zn 2+ to inhibit the replication of various RNA viruses has been demonstrated in a good number of in vitro studies. For example, in the presence of its cellular import stimulatory compounds such as hinokitol (HK), pyrrolidine dithiocarbamate (PDTC), and pyrithione (PT), the added Zn 2+ inhibited the replication of influenza virus [73], respiratory syncytial virus [74], and several picornaviruses [71,75,76]. Their interference with polyprotein processing in cells infected with human rhinovirus and coxsackievirus B3 is well evidenced [71]. ...
... For example, in the presence of its cellular import stimulatory compounds such as hinokitol (HK), pyrrolidine dithiocarbamate (PDTC), and pyrithione (PT), the added Zn 2+ inhibited the replication of influenza virus [73], respiratory syncytial virus [74], and several picornaviruses [71,75,76]. Their interference with polyprotein processing in cells infected with human rhinovirus and coxsackievirus B3 is well evidenced [71]. ...
Article
Full-text available
As far as comorbidity is concerned, cardiovascular diseases (CVD) appear to be accounted for the highest prevalence, severity, and fatality among COVID 19 patients. A wide array of causal links connecting CVD and COVID-19 baffle the overall prognosis as well as the efficacy of the given therapeutic interventions. At the centre of this puzzle lies ACE2 that works as a receptor for the SARS-CoV-2, and functional expression of which is also needed to minimize vasoconstriction otherwise would lead to high blood pressure. Furthermore, SARS-CoV-2 infection seems to reduce the functional expression of ACE2. Given these circumstances, it might be advisable to consider a treatment plan for COVID-19 patients with CVD in an approach that would neither aggravate the vasodeleterious arm of the renin-angiotensinogen-aldosterone system (RAAS) nor compromise the vasoprotective arm of RAAS but is effective to minimize or if possible, inhibit the viral replication. Given the immune modulatory role of Zn in both CVD and COVID-19 pathogenesis, zinc supplement to the selective treatment plan for CVD and COVID-19 comorbid conditions, to be decided by the clinicians depending on the cardiovascular conditions of the patients, might greatly improve the therapeutic outcome. Notably, ACE2 is a zinc metalloenzyme and zinc is also known to inhibit viral replication.
... It has been known for many years that some metals, such as Zn(II), Cu(II), Mg and Mn(II) have antiviral properties (Perrin and Stünzi, 1981;Chaturvedi and Shrivastava, 2005;Krenn et al., 2009;Ishida, 2018a;Ishida, 2018;Ishida, 2019). Metal ions play an important role in the survival and pathogenesis of a large group of viruses. ...
... Analysis of the structure of metal binding to viral proteins will certainly be useful in the design of virus inhibitors (reverse transcriptase-RT, protease, integrase, nucleoside inhibitors) (Perrin and Stünzi, 1981;Chaturvedi and Shrivastava, 2005;Ishida, 2018). Studies have shown that Zn(II) ions ihibited the in vitro activity of nidovirus polymerases, the action of the SARS-CoV RNA-dependent RNA polymerase (RdRp) and synthesis of foot-and-mouth disease virus (FMDV) components such as RNA and procapsid (Krenn et al., 2009;Ishida, 2018). In addition, zinc ions are potent inhibitors of the fusion stage of several alphaviruses (Ishida, 2018a). ...
Article
Full-text available
The coronavirus pandemic (SARS CoV-2) that has existed for over a year, constantly forces scientists to search for drugs against this virus. In silico research and selected experimental data have shown that compounds of natural origin such as phenolic acids and flavonoids have promising antiviral potential. Phenolic compounds inhibit multiplication of viruses at various stages of the viral life cycle, e.g., attachment (disturbance of the interaction between cellular and viral receptors), penetration (inhibition of viral pseudo-particle fusion to the host membrane), replication (inhibition of integrase and 3C-like protease), assembly and maturation (inhibition of microsomal triglyceride transfer protein (MTP) activity hydrolysis) and release (inhibition of secretion of apolipoprotein B (apoB) from infected cells). Phenolic compounds also indirectly influence on the viral life cycle by affecting the host cell’s biochemical processes that viruses use for their own benefit. Phenolic compounds may inhibit the proteasomes and cellular deubiquitinating activity that causes an increase in the ubiquitinated proteins level in host cells. This, in turn, contributes to the lowering the available ubiquitin molecules that viruses could use for their own replication. One of the drug design strategy for the treatment of viral diseases may be an enhancement of the antiviral properties of phenolic compounds by metal complexation. Many studies have shown that the presence of a metal ion in the structure can significantly affect the affinity of the compound to key structural elements of the SARS CoV-2, such as Mpro protease, RNA-dependent RNA polymerase (RdRp) and spike protein. We believe that in the era of coronavirus pandemic, it is necessary to reconsider the search for therapeutics among well-known compounds of plant origin and their metal complexes.
... PDTC affects influenza viruses [75], rhinovirus [76], poliovirus, and mengovirus [77]. The last three viruses are also inhibited by HK in the presence of Zn [78]. HK, a tropolone derivative, is a natural monoterpenoid found in the wood of trees in the family Cupressaceae. ...
... PT also possesses a good antiviral activity against a number of RNA viruses and DNA viruses such as human rhinovirus, coxsackievirus, mengovirus, and HSV [78]. In particular, its ability to inhibit HSV-1 and HSV-2 has been related to a Zn-dependent action [80]. ...
Article
Zinc can play a pathophysiological role in several diseases and can interfere in key processes of microbial growth. This evidence justifies the efforts in applying Zinc ionophores to restore Zinc homeostasis and treat bacterial/viral infections such as coronavirus diseases. Zinc ionophores increase the intracellular concentration of Zinc ions causing significant biological effects. This review provides, for the first time, an overview of the applications of the main Zinc ionophores in Zinc deficiency, infectious diseases, and in cancer, discussing the pharmacological and coordination properties of the Zinc ionophores.
... An increased intracellular concentration of Zn ions in combination with Zn ionophores such as pyrithione has been reported to serve as an effective inhibitor of various RNA viruses by blocking the activity of RdRP [28,62] [ 28 ,62 ]. RdRPs catalyze the RNA template-dependent formation of phosphodiester bonds between ribonucleotides. ...
... RdRPs catalyze the RNA template-dependent formation of phosphodiester bonds between ribonucleotides. Several cell-based studies have also revealed that exposure to zinc in the presence of its cellular import stimulatory compounds, including hinokitol (HK), pyrrolidine dithiocarbamate (PDTC), and pyrithione, reduces the replication process of RNA viruses [29,31,34,62,63] [ 29 , 31 , 34 , 62 , 63 ]. An in vitro study verified that the addition of Zn 2 + with pyrithione potentially suppresses the replication of SARS-CoV-1 [28] [28] . ...
Article
Novel coronavirus disease 2019 (COVID-19) has spread across the globe; and surprisingly, no potentially protective or therapeutic antiviral molecules are available to treat severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, zinc (Zn) and copper (Cu) have been shown to exert protective effects due to their antioxidant, anti-inflammatory and antiviral properties. Therefore, it is hypothesized that supplementation with Zn and Cu alone or as an adjuvant may be beneficial with promising efficacy and a favorable safety profile to mitigate symptoms, as well as halt progression of the severe form of SARS-CoV-2 infection. The objective of this review is to discuss the proposed underlying molecular mechanisms and their implications for combating SARS-CoV-2 infection in response to Zn and Cu administration. Several clinical trials have also included the use of Zn as an adjuvant therapy with dietary regimens/antiviral drugs against COVID-19 infection. Overall, this review summarizes that nutritional intervention with Zn and Cu may offer an alternative treatment strategy by eliciting their virucidal effects through several fundamental molecular cascades, such as, modulation of immune responses, redox signaling, autophagy, and obstruction of viral entry and genome replication during SARS-CoV-2 infection.
... Hinokitiol and pyrithione are two zinc ionophores involved in the import of extracellular zinc into the cytosol, increasing intracellular zinc concentrations. Therefore, disturbance of the proteolytic processing of viral polyproteins will efficiently impair the replication of RNA viruses [103]. According to Hoang et al., hinokitiol can be utilized in the prevention and treatment of COVID-19 and other respiratory viral infections [86]. ...
... Such findings indicate that zinc can be considered as a particular antiviral factor in the therapy of SARS-CoV-2 infection. According to a separate set of studies, zinc ions probably are localized into the mitochondria and the corresponding inhibition mechanism remains uncertain [103]. However, the mechanisms underlying zinc antiviral activity in COVID-19 require further researches [69] (Fig. 1). ...
Article
The novel SARS-CoV-2 which was first reported in China is the cause of infection known as COVID-19. In comparison with other coronaviruses such as SARS-CoV and MERS, the mortality rate of SARS-CoV-2 is lower but the transmissibility is higher. Immune dysregulation is the most common feature of the immunopathogenesis of COVID-19 that leads to hyperinflammation. Micronutrients such as zinc are essential for normal immune function. According to the assessment of WHO, approximately one-third of the world’s society suffer from zinc deficiency. Low plasma levels of zinc are associated with abnormal immune system functions such as impaired chemotaxis of polymorphonuclear cells (PMNs) and phagocytosis, dysregulated intracellular killing, overexpression of the inflammatory cytokines, lymphopenia, decreased antibody production, and sensitivity to microbes especially viral respiratory infections. Zinc exerts numerous direct and indirect effects against a wide variety of viral species particularly RNA viruses. The use of zinc and a combination of zinc-pyrithione at low concentrations impede SARS-CoV replication in vitro. Accordingly, zinc can inhibit the elongation step of RNA transcription. Furthermore, zinc might improve antiviral immunity by up-regulation of IFNα through JAK/STAT1 signaling pathway in leukocytes. On the other hand, zinc supplementation might ameliorate tissue damage caused by mechanical ventilation in critical COVID-19 patients. Finally, zinc might be used in combination with antiviral medications for the management of COVID-19 patients. In the current review article, we review and discuss the immunobiological roles and antiviral properties as well as the therapeutic application of zinc in SARS-CoV-2 and related coronaviruses infections.
... They are increase zinc concentration in intracellular place. Hence, viral polyprotein will effectively weaken the replication of RNA virus for disturbance of proteolytic processing (Krenn et al., 2009) [27] . The new study demonstrates that chloroquine is a zinc ionophore that increases the flow of zinc into the cell (Xue et al., 2014) [55] . ...
... They are increase zinc concentration in intracellular place. Hence, viral polyprotein will effectively weaken the replication of RNA virus for disturbance of proteolytic processing (Krenn et al., 2009) [27] . The new study demonstrates that chloroquine is a zinc ionophore that increases the flow of zinc into the cell (Xue et al., 2014) [55] . ...
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The global pandemic coronavirus disease has created a chaotic situation all over the world. This is happened due to SARS-CoV-2 infection, which is spread through we human to human connection. Now different countries have discovered vaccines for coronavirus. At the same time our body needs its own immune system. For these reasons immune boosting substance are also required. This review paper indicates that zinc acts as an immune booster in our body against the coronavirus disease. In addition, it is also an immunomodulatory and immunosuppressive component. On one hand zinc has antioxidant properties, which can remove the free radicals from our body with increasing fluidity of the cell membrane. This may result, improve the lymphocyte's function. Depending on this information it is clear that zinc have the power of create resistance barrier against coronavirus infection.
... The unique phenotypic characteristics of viruses [616] requires the antiviral mechanisms of ionophores to be distinct from mechanisms that affect prokaryotes or eukaryotes. Such mechanisms range from interference with viral polyprotein processing and promotion of antioxidative activity [120,340] to inhibition of viral entry [346], receptor binding [617] or viral replication [618]. Ionophores such as Valinomycin have demonstrated broad bioavailability and antiviral properties while significantly reducing viral titres [332]. ...
... Unfortunately, research on ionophore activity against viruses generally remains limited, with published studies mostly containing in vitro data [120,332,343,346]. While several ionophores have displayed promising antiviral activities across a broad spectrum of viral classes ( Table 4), further research is required to investigate whether these compounds, such as Disulfiram, can be successfully translated into human therapies. ...
Article
Ionophores are a diverse class of synthetic and naturally occurring ion transporter compounds which demonstrate both direct and in-direct antimicrobial properties against a broad panel of bacterial, fungal, viral and parasitic pathogens. In addition, ionophores can regulate the host-immune response during communicable and non-communicable disease states. Although the clinical use of ionophores such as Amphotericin B, Bedaquiline and Ivermectin highlight the utility of ionophores in modern medicine, for many other ionophore compounds issues surrounding toxicity, bioavailability or lack of in vivo efficacy studies have hindered clinical development. The antimicrobial and immunomodulating properties of a range of compounds with characteristics of ionophores remain largely unexplored. As such, ionophores remain a latent therapeutic avenue to address both the global burden of antimicrobial resistance, and the unmet clinical need for new antimicrobial therapies. This review will provide an overview of the broad-spectrum antimicrobial and immunomodulatory properties of ionophores, and their potential uses in clinical medicine for combatting infection.
... 99 However, the concentration of Zn ion in blood serum and the intracellular system is controlled by Metallothionein's, a group of small cysteine-rich proteins that play an important role in metal homeostasis and protection against heavy metal toxicity, oxidative stress, and DNA damage. 100 Excessive levels of Zn 2+ ion in the metabolic system may trigger apoptosis or a decrease in protein synthesis. 101,102 In some previous in vitro studies, it has been observed that Zn 2+ concentrations higher than usual and compounds that stimulate cellular import of Zn 2+ (hinokitol, pyrrolidine dithiocarbamate, and pyrithione) inhibit the replication of various RNA viruses (corona virus, influenza virus, respiratory syncytial virus, picornaviruses, arterivirus) by blocking RNA polymerase enzymes. ...
... 101,102 In some previous in vitro studies, it has been observed that Zn 2+ concentrations higher than usual and compounds that stimulate cellular import of Zn 2+ (hinokitol, pyrrolidine dithiocarbamate, and pyrithione) inhibit the replication of various RNA viruses (corona virus, influenza virus, respiratory syncytial virus, picornaviruses, arterivirus) by blocking RNA polymerase enzymes. 100,103 One study indicates that Hesperidin (found in many fruit peels) could be a potential antiviral to target the interaction site between SARS-CoV-2 Spike and ACE2 receptors, preventing infection of lung cells. 104,105 Another study indicates that Hesperidin-mediated ZnO NPs (25 nm) exhibit antiviral activity against SARS-CoV-2 like RNA virus (Hepatitis A) more than hesperidin alone at maximum noncytotoxic concentration. ...
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The COVID-19 pandemic caused by the SARS-CoV-2, a Ribonucleic acid (RNA) virus that emerged less than two years but has caused nearly 6.1 million deaths to date. Recently developed variants of the SARS-CoV-2 virus have been shown to be more potent and expanded at a faster rate. Till now there is no specific and effective treatment for SARS-CoV-2 in terms of reliable and sustainable recovery. Precaution, prevention, and vaccinations are the only ways to keep the pandemic situation under control. Medical and scientific professionals are now focusing on the repurposing of previous technology and trying to develop more fruitful methodologies to detect the presence of viruses, treat the patients, precautionary items, and vaccine developments. Nanomedicine or nano-based platforms can play a crucial role in these fronts. Researchers are working on many effective approaches by nanosized particles to combat SARS-CoV-2. The role of a nano-based platform to combat SARS- CoV-2 is extremely diverse (i.e., mark to personal protective suit, rapid diagnostic tool to targeted treatment, and vaccine developments). Although there are many theoretical possibilities of a nano- based platform to combat SARS-CoV-2, till now there is an inadequate number of research targeting SARS-CoV-2 to explore such scenarios. This unique mini-review aims to compile and elaborate on the recent advances of nano-based approaches from prevention, diagnostics, treatment to vaccine developments against SARS-CoV-2 and associated challenges.
... Specifically, ageing, immune deficiency, as well as metabolic diseases such as obesity, diabetes, and atherosclerosis, are known to be both risk factors for high disease mortality (96,97) and zinc deficiency (98). In turn, Zn supplementation may have beneficial effect in modulation of at least some of these risk factors.(99,100) ...
... Using a combination of 10 μg/mL punicalagin and 3 mg/mL Zn sulfate monohydrate, we noticed a significant decrease in 3CL-protease activity (p < 0.001), while not causing recognizable cytotoxicity. Inhibition of replication induced by pyrithione and Zn 2+ over a range from 2 to 10 µM was recently reported for a few picornaviruses, for example, rhinoviruses, foot-and-mouth infections, coxsackievirus, and mengovirus 22,23 . ...
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Abstract. – OBJECTIVE: Coronavirus 2019 (COVID-19) has now been declared as a world-wide pandemic. Currently, no drugs have been endorsed for its treatment; in this manner, a pressing need has been developed for any antiviral drugs that will treat COVID-19. Coronaviruses require the SARS-CoV-2 3CL-Protease (3CL-protease) for cleavage of its polyprotein to yield a single useful protein and assume a basic role in the disease progression. In this study, we demonstrated that punicalagin, the fundamental active element of pomegranate in addition to the combination of punicalagin with zinc (Zn) II, appear to show powerful inhibitory activity against SARS-CoV-2. MATERIALS AND METHODS: The 3CL protease assay kit was used to quantify 3CL protease action. The tetrazolium dye, MTS, was used to evaluate cytotoxicity. RESULTS: Punicalagin showed inhibitory action against the 3CL-protease in a dose-dependent manner, and IC50 was found to be 6.192 μg/ml for punicalagin. Punicalagin (10 µg/mL) demonstrated a significant inhibitory activity toward 3CL-protease activity (p < 0.001), yet when punicalagin is combined with zinc sulfate monohydrate (punicalagin/Zn-II) extremely strong 3CL-protease activity (p < 0.001) was obtained. The action of 3CL-protease with punicalagin/Zn-II was decreased by approximately 4.4-fold in contrast to only punicalagin (10 µg/mL). Likewise, we did not notice any significant cytotoxicity caused by punicalagin, Zn-II, or punicalagin/Zn-II. CONCLUSIONS: We suggest that these compounds could be used as potential antiviral drugs against COVID-19. Key Words: Punicalagin, Zinc II, SARS-CoV-2 3CL-Protease, SARS-CoV-2, COVID-19
... Using a combination of 10 μg/mL punicalagin and 3 mg/mL Zn sulfate monohydrate, we noticed a significant decrease in 3CL-protease activity (p < 0.001), while not causing recognizable cytotoxicity. Inhibition of replication induced by pyrithione and Zn 2+ over a range from 2 to 10 µM was recently reported for a few picornaviruses, for example, rhinoviruses, foot-and-mouth infections, coxsackievirus, and mengovirus 22,23 . ...
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OBJECTIVE: Coronavirus 2019 (COVID-19) has now been declared as a worldwide pandemic. Currently, no drugs have been endorsed for its treatment; in this manner, a pressing need has been developed for any an-tiviral drugs that will treat COVID-19. Corona-viruses require the SARS-CoV-2 3CL-Protease (3CL-protease) for cleavage of its polyprotein to yield a single useful protein and assume a basic role in the disease progression. In this study, we demonstrated that punicalagin, the fundamental active element of pomegranate in addition to the combination of punicalagin with zinc (Zn) II, appear to show powerful inhibitory activity against SARS-CoV-2. MATERIALS AND METHODS: The 3CL prote-ase assay kit was used to quantify 3CL protease action. The tetrazolium dye, MTS, was used to evaluate cytotoxicity. RESULTS: Punicalagin showed inhibitory action against the 3CL-protease in a dose-dependent manner, and IC50 was found to be 6.192 μg/ml for punicalagin. Punicalagin (10 µg/ mL) demonstrated a significant inhibitory activity toward 3CL-protease activity (p < 0.001), yet when punicalagin is combined with zinc sul-fate monohydrate (punicalagin/Zn-II) extremely strong 3CL-protease activity (p < 0.001) was obtained. The action of 3CL-protease with pu-nicalagin/Zn-II was decreased by approximately 4.4-fold in contrast to only punicalagin (10 µg/ mL). Likewise, we did not notice any significant cytotoxicity caused by punicalagin, Zn-II, or pu-nicalagin/Zn-II. CONCLUSIONS: We suggest that these compounds could be used as potential antiviral drugs against COVID-19.
... Using a combination of 10 μg/mL punicalagin and 3 mg/mL Zn sulfate monohydrate, we noticed a significant decrease in 3CL-protease activity (p < 0.001), while not causing recognizable cytotoxicity. Inhibition of replication induced by pyrithione and Zn 2+ over a range from 2 to 10 µM was recently reported for a few picornaviruses, for example, rhinoviruses, foot-and-mouth infections, coxsackievirus, and mengovirus 22,23 . ...
Article
Full-text available
Objective: Coronavirus 2019 (COVID-19) has now been declared as a worldwide pandemic. Currently, no drugs have been endorsed for its treatment; in this manner, a pressing need has been developed for any antiviral drugs that will treat COVID-19. Coronaviruses require the SARS-CoV-2 3CL-Protease (3CL-protease) for cleavage of its polyprotein to yield a single useful protein and assume a basic role in the disease progression. In this study, we demonstrated that punicalagin, the fundamental active element of pomegranate in addition to the combination of punicalagin with zinc (Zn) II, appear to show powerful inhibitory activity against SARS-CoV-2. Materials and methods: The 3CL protease assay kit was used to quantify 3CL protease action. The tetrazolium dye, MTS, was used to evaluate cytotoxicity. Results: Punicalagin showed inhibitory action against the 3CL-protease in a dose-dependent manner, and IC50 was found to be 6.192 μg/ml for punicalagin. Punicalagin (10 µg/mL) demonstrated a significant inhibitory activity toward 3CL-protease activity (p < 0.001), yet when punicalagin is combined with zinc sulfate monohydrate (punicalagin/Zn-II) extremely strong 3CL-protease activity (p < 0.001) was obtained. The action of 3CL-protease with punicalagin/Zn-II was decreased by approximately 4.4-fold in contrast to only punicalagin (10 µg/mL). Likewise, we did not notice any significant cytotoxicity caused by punicalagin, Zn-II, or punicalagin/Zn-II. Conclusions: We suggest that these compounds could be used as potential antiviral drugs against COVID-19.
... research, it may inhibit RNA polymer, which needs further study (66,67). Various vitamins are involved in different stages of the immune response by the following possible mechanisms: Vitamin A plays a key role in boosting the function of innate immune cells, such as neutrophils, macrophages, NK cells, and boosting the antibody response (68,69). ...
Article
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Background Although previous studies observed the relationship between individual dietary supplements and enhancing body resistance against viruses, few studies have been conducted regarding the role of different supplements in treatment of COVID-19. This article aims to determine the association of recent and long-term supplement consumption on the biochemical indices and impatient duration among patients with COVID-19. Methods In this cross-sectional study on 300 adult men and women with COVID-19, recent and long-term supplement intakes were investigated by using a questionnaire. In addition, lifestyle was also assessed in aspects of fruits and vegetable consumption, physical activity, sleeping duration, fluid intake, and smoking status. Furthermore, the laboratory and paraclinical parameters were obtained from medical records. The relationship between supplement intake with the length of hospitalization and clinical laboratory tests was investigated by one-way analysis of variance (ANOVA). Results Those patients with supplement intake in the last 2 months had a significantly lower amount of blood urea nitrogen (BUN) (31.31 ± 13.87 vs. 37.57 ± 19.77 mg/dL, P : 0.002) and higher serum 25(OH)D (28.13 ± 14.09 vs. 23.81 ± 13.55 ng/mL, P : 0.03). Subjects with long-term supplement intake had a significantly lower invasive oxygen support (0.00 vs 5.10 %, P : 0.05), lactate dehydrogenase (LDH) (498.11 ± 221.43 vs. 576.21 ± 239.84 U/L, P: 0.02), fewer days of fever (0.49 ± 3.54 vs. 2.64 ± 9.21, P : 0.02), and higher serum 25(OH)D (31.03 ± 13.20 vs. 22.29± 13.42 ng/mL, P < 0.001). The length of hospital stay was practically the same between groups who received and did not receive supplementation during the 2 months prior to hospitalization (6.36 ± 3.32 vs. 6.71 ± 4.33 days, P : 0.004). Similarly, people who took supplements during the past year had practically similar hospitalization lengths (6.29 ± 4.13 vs. 6.74 ± 3.55 days, P : 0.004). Conclusion In conclusion, although practically the length of hospital stay was the same in both groups of supplement consumers and others, immune-boosting supplements were associated with improved several laboratory indices. However, due to the cross-sectional nature of our study, further longitudinal studies seem to be essential.
... Seipelt and colleagues demonstrated the activity of zinc ionophores Pyrithione (PT) and Hinokitiol (HK) against multiplication of human rhinoviruses, coxsackievirus, and mengovirus. [22] These compounds inhibited the replication of picornaviruses considerably by impairing viral polyprotein processing. ...
Article
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Several life‐threatening diseases, also known as ‘Channelopathies’ are linked to irregularities in ion transport proteins. Significant research efforts have fostered the development of artificial transport systems that facilitates to restore the functions of impaired natural transport proteins. Indeed, a few of these artificial ionophores demonstrate the rare combination of transmembrane ion transport and important biological activity, offering early promises of suitability in ‘channel replacement therapy’. In this review, structural facets and functions of both cationophores and anionophores are discussed. Ionophores that are toxic to various bacteria and yeast, could be exploited as antimicrobial agent. Nevertheless, few non‐toxic ionophores offer the likelihood of treating a wide range of genetic diseases caused by the gene mutations. In addition, their ability to disrupt cellular homeostasis and to alter lysosomal pH endow ionophores as promising candidates for cancer treatment. Overall, critically outlining the advances in artificial ionophores in terms of in vitro ion transport, possible modes of action and biological activities enables us to propose possible future roadmaps in this research area.
... The antiviral effects of zinc have been demonstrated against several human viruses. Increasing the intracellular zinc concentration with zinc-ionophores like pyrithione was reported to impair viral replication in vitro [32,33]. Recent studies have shown the efficacy of chloroquine, a zinc ionophore, as an antiviral treatment for COVID-19 (20). ...
Article
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Zinc is an indispensable trace element required for several critical functions of the human body. Deficiencies of micronutrients can impair immune function and increase susceptibility to infectious disease. It is noteworthy that higher susceptibility to the SARS-CoV-2 viral infection is seen in individuals with micronutrient deficiencies and poorer overall nutrition. Research in the last two decades suggests that one-third of the global population may be deficient in zinc, which affects the health and well-being of individuals of all ages and gender. Zinc deficiency is now considered one of the factors associated with susceptibility to infection and the detrimental progression of COVID-19. The trace element is essential for immunocompetence and antiviral activity, rendering zinc supplements highly popular and widely consumed. Zinc supplements are required in small doses daily, and their absorption is affected by food rich in fiber and phytase. The organic forms of zinc such as picolinate, citrate, acetate, gluconate, and the monomethionine complexes are better absorbed and have biological effects at lower doses than inorganic salts. Considering the present global scenario, choosing the right zinc supplement is essential for maintaining good health. In the present review, we reexamine the role of zinc in immunity and antiviral activity and a comparative account of different forms of zinc supplements.
... The trace metal zinc (Zn), is known for its effect on physical growth, but it has anti-viral properties too (Read et al., 2019). Increased intracellular Zn concentrations are known to efficiently impair replication of a number of RNA viruses, such as SARS-CoV-2, for example, by interfering with correct proteolytic processing of viral polyproteins (Gaudernak et al., 2002;Krenn et al., 2009;Korant et al., 1974;Lanke et al., 2007;Polatnick and Bachrach, 1978;Si et al., 2005;Uchide et al., 2002). te Velthuis et al. (2010) demonstrated that coronavirus and arteri-virus replication can be inhibited by increased Zn levels via inhibition of virus RdRps (RNA-dependent RNA polymerase). ...
Article
Background In late December 2019, the outbreak of COVID-19 caused by the coronavirus severe acute respiratory syndrome-CoV-2, originated in Wuhan Province, the People’s Republic of China (PRC). The rapid and highly infectious virus quickly spread around the country and has become a global pandemic. Thousands of people have been infected, and have died. Scientists around the world are working on the vaccine; however, an effective cure is yet to be developed. Aims Search to be made on some alternative antiviral components from the rich sources of traditional herbal medicine in India as well as in the PRC. Here we discuss them with references. Methods The knowledge gained from the literature search of antiviral known herbal products or Ayurvedic medicines that used to be applied against any viral or bacterial infections in the past, may be considered for deployment against COVID-19, and may be rewarded. Results Many medicinal compounds are extracted from plants and have led to drug discovery. Similarly, plant products and their analogues have been employed as an early line of defense against COVID-19. Conclusion Research into ethnobotany, phytochemistry, plant physiology and ecology may be important in protecting the global population from current and future pandemics.
... Ionophores may move 'to' and 'fro' between the cytoplasm or could as well remain in the plasma membrane as it transports metal ions. (Krenn et al., 2009;Qiu et al., 2013). ...
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Covid 19 pandemic has been established to be caused by the novel SARS-CoV-2 and like most major viral outbreaks has posed enormous challenges of which different scientific and clinical approaches have been proposed. One approach to the inhibition and control of SARS-CoV-2 invasion is through pH regulated zinc ionophores. This work reviews current information on the background of the SARS-CoV2 pandemic, the key proteins that make up the peculiar structure of the virus and highlights the mechanism of invasion mainly from the binding of the S proteins of SARS-CoV-2 to the human angiotensin-converting enzyme 2 (ACE2). It explores the concept of pH regulated ionophores focusing on the mechanisms and regulation of zinc ionophores geared towards the inhibition and control of SARS-COV-2 invasion. The work then highlights the inhibitory mechanism of chloroquine on SARS-CoV-2 replication giving more depth to the proposition for its use in the treatment of the viral infection.
... Indeed, zinc was previously considered a potential agent for the prevention of H1N1 influenza ("swine flu") and has direct antiviral properties [134]. Studies have shown that the replication of severe acute respiratory syndrome coronavirus (SARS-CoV) and hepatitis C virus (HCV) was inhibited by zinc oxide or zinc salt, while zinc could be deposited onto the surfaces of herpes simplex virus (HSV) virions, and the viral ubiquitin-proteasome pathway could be targeted with the zinc ionophore pyrithione to inhibit HSV-1 and HSV-2 infections [14,[135][136][137]. Upon exposure to low endosomal pH, zinc binding with a specific histidine residue on the viral E1 protein can effectively inhibit membrane fusion and block particle release of respiratory syncytial virus, HSV, Semliki Forest virus, and sindbis viruses [138,139]. ...
Article
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Zinc (Zn) is an essential trace element in living organisms and plays a vital role in the regulation of both microbial virulence and host immune responses. A growing number of studies have shown that zinc deficiency or the internal Zn concentration does not meet the needs of animals and microbes, leading to an imbalance in zinc homeostasis and intracellular signalling pathway dysregulation. Competition for zinc ions (Zn2+) between microbes and the host exists in the use of Zn2+ to maintain cell structure and physiological functions. It also affects the interplay between microbial virulence factors and their specific receptors in the host. This review will focus on the role of Zn in the crosstalk between the host and microbe, especially for changes in microbial pathogenesis and nociceptive neuron-immune interactions, as it may lead to new ways to prevent or treat microbial infections.
... Zinc, a vital element for human health, has demonstrated antiviral activity for other respiratory viruses (Suara and Crowe, 2004;Krenn, 2009), and has been proposed as a treatment for SARS-CoV-2 (Wessels et al., 2020). Zinc deficiency is common in the elderly (Fosmire, 1990;Kvamme et al., 2015) and has been correlated with increased severity of COVID infection (Jothimani et al., 2020), and advanced age is the strongest risk factor for death from COVID-19 (Centers for Disease Control and Prevention, 2019). ...
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Background: Safe, effective, and inexpensive treatment for COVID-19 is an urgent unmet medical need. Zinc and resveratrol have been reported to have antiviral activity, and resveratrol may increase zinc activity at the site of replication by increasing intracellular zinc concentrations. Methods: A 1:1 randomized, placebo-controlled trial of zinc 150 mg plus resveratrol 4 g daily for 5 days versus placebos in outpatients with SARS-CoV-2 was carried out from 9/21/2020–1/22/2021 in Seattle, Washington. Viral shedding was followed with patient self-collected nasal and saliva samples by measuring qRT-PCR for SARS-CoV-2 N gene days 1–7, 10, and 14. Patients filled out a web-based questionnaire on days 1–14 to report symptoms, vital signs and adherence to the study intervention. The study was posted as Clinical Trials.gov NCT04542993 on 9 September 2020. Results: A total of 30 participants (14 treatment; 16 placebos) had ≥1 day of the protocol treatment and were evaluable for the primary or secondary outcome. There was no difference in viral shedding between groups, nor in the resolution of symptoms. There was a trend toward a more rapid decrease in symptoms in the treatment group, though this was not statistically significant in the GLM model. Viral shedding was similar between patient self-collected mid-turbinate nasal swabs and expectorated saliva samples with a good correlation. Conclusion: SARS-CoV-2 shedding and COVID-19 symptoms were not statistically significantly decreased by treatment. Viral shedding correlates well between patient-obtained home nasal swabs and saliva sampling.
... There is evidence that zinc can increase the effect of chloroquine (zinc ionophore) as a therapeutic drug, and another zinc ionophore, such as epigallocatechin gallate aur quercetin, are being tested [243]. Various studies have also shown that low concentrations of zinc supplementation along with ionophore pyrithione or inositol reduce the synthesis of SARS-CoV-2 RNA by direct inhibition of RNA-dependent RNA polymerase [244,245]. ...
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COVID-19 is a rapidly spreading disease, which has caught the world by surprise. Millions of people suffer from illness, and the mortality rates are dramatically high. Currently, there is no specific and immediate treatment for this disease. Remedies are limited to supportive regiments and few antiviral and anti-inflammatory drugs. The lack of a definite cure for COVID-19 is the reason behind its high mortality and global prevalence. COVID-19 can lead to a critical illness with severe respiratory distress and cytokine release. Increased oxidative stress and excessive production of inflammatory cytokines are vital components of severe COVID-19. Micronutrients, metalloids, and vitamins such as iron, manganese, selenium, Zinc, Copper, vitamin A, B family, and C are among the essential and trace elements that play a pivotal role in human nutrition and health. They participate in metabolic processes that lead to energy production. In addition, they support immune functions and act as antioxidants. Therefore, maintaining an optimal level of micronutrients intake, particularly those with antioxidant activities, is essential to fight against oxidative stress, modulate inflammation, and boost the immune system. Therefore, these factors could play a crucial role in COVID-19 prevention and treatment. In this review, we aimed to summarize antiviral properties of different vitamins and minerals. Moreover, we will investigate the correlation between them and their effects in COVID-19 patients.
... This can be achieved via viral particle entry modulation, replication, translation of viral protein, fusion, and additional release for some viruses (Ishida, 2019;Read, Obeid, Ahlenstiel, & Ahlenstiel, 2019). It was concluded that the increment of intracellular Zn levels via the usage of Zn ionophores considerably changes picornavirus replication (Krenn et al., 2009). These conclusions were from earlier studies from around the 1970s (Korant, Kauer, & Butterworth, 1974). ...
Article
In 2019, a novel type of coronavirus emerged in China called SARS-COV-2, known COVID-19, threatens global health and possesses negative impact on people's quality of life, leading to an urgent need for its diagnosis and remedy. On the other hand, the presence of hazardous infectious waste led to the increase of the risk of transmitting the virus by individuals and by hospitals during the COVID-19 pandemic. Hence, in this review, we survey previous researches on nanomaterials that can be effective for guiding strategies to deal with the current COVID-19 pandemic and also decrease the hazardous infectious waste in the environment. We highlight the contribution of nanomaterials that possess potential to therapy, prevention, detect targeted virus proteins and also can be useful for large population screening, for the development of environmental sensors and filters. Besides, we investigate the possibilities of employing the nanomaterials in antiviral research and treatment development, examining the role of nanomaterials in antiviral- drug design, including the importance of nanomaterials in drug delivery and vaccination, and for the production of medical equipment. Nanomaterials-based technologies not only contribute to the ongoing SARS- CoV-2 research efforts but can also provide platforms and tools for the understanding, protection, detection and treatment of future viral diseases.
... RNA polymerase) activity (36)(37)(38)(39)(40)(41)(42)(43). The infection of virus and other pathogens, Zn is directly or indirectly triggering the host immune response. ...
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Currently, the novel and major life-threatening cause all over the world is COVID-19 (Coronavirus disease 2019) which is started at the end of 2019 in Wuhan, China, and spread all over the world today. The infection of COVID-19 severity is variable which affects all ages' people and especially elderly persons whose immune system is very weak. Fatigue, fever, respiratory illness, dry cough, loss of appetite, olfactory dysfunction are the most common symptoms of this disease along with the decrease of certain cells of the immune system like helper T cells, monocytes/macrophages, etc. and an increase in pro-inflammatory cytokines are some of the major characteristics of this disease. Some natural herbal products are a successive option to combat SARS-Cov-2 disease. Herbs have various potential compound which is used as a dietary product that strongly influences immunity and maintenance of the homeostasis of inflammatory/anti-inflammatory. In the present review, we describe the potential of three herbal products as Turmeric (Haldi), Heart-leaved moonseed (Giloy), and Black cumin (Kalonji) that can be used for preventative or nutritional therapy of COVID-19.
... Importantly, it is known to possess antiviral properties against many different viruses, namely, herpes simplex virus (HSV), severe acute respiratory syndrome coronavirus (SARS CoV), rhinovirus, respiratory syncytial virus (RSV), equine arteritis virus (EAV), human papilloma virus (HPV), human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis E virus (HEV) (Korant et al., 1974;Haraguchi et al., 1999;Suara and Crowe Jr, 2004;Te Velthuis et al., 2010;Kaushik et al., 2017). Multiple mechanisms underlie the antiviral activity of zinc, which includes inhibition of virus entry and viral polyprotein processing or inhibition of viral RNA dependent RNA polymerase activity (Haraguchi et al., 1999;Krenn et al., 2009;Te Velthuis et al., 2010;Kaushik et al., 2017). Zinc also contributes toward modulating the host immune response to restrict viral replication. ...
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Hepatitis E virus (HEV) causes an acute, self-limiting hepatitis. The disease takes a severe form in pregnant women, leading to around 30% mortality. Zinc is an essential micronutrient that plays a crucial role in multiple cellular processes. Our earlier findings demonstrated the antiviral activity of zinc salts against HEV infection. Zinc oxide (ZnO) and its nanostructures have attracted marked interest due to their unique characteristics. Here we synthesized ZnO nanoparticles [ZnO(NP)] and tetrapod-shaped ZnO nanoparticles [ZnO(TP)] and evaluated their antiviral activity. Both ZnO(NP) and ZnO(TP) displayed potent antiviral activity against hepatitis E and hepatitis C viruses, with the latter being more effective. Measurement of cell viability and intracellular reactive oxygen species levels revealed that both ZnO(NP) and ZnO(TP) are noncytotoxic to the cells even at significantly higher doses, compared to a conventional zinc salt (ZnSO4). Our study paves the way for evaluation of the potential therapeutic benefit of ZnO(TP) against HEV and HCV.
... Later, hinokitiol (2-Hydroxy-4-isopropyl-2,4,6cycloheptatrien-1-one; C 10 H 12 O 2 ), also known as beta-thujaplicin, was identified in several other cupressaceous plants [1][2][3]. Hinokitiol has been recognized as a multi-potential pharmaceutical agent, with anti-inflammatory, anti-bacterial, and anti-fungal activities [2,[4][5][6][7][8]. ...
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Background: Hinokitiol (β-thujaplicin), isolated from the wood of Chamaecyparis taiwanensis, has a wide variety of biological properties including anti-inflammatory, anti-microbial, and anti-tumor effects. Therefore, hinokitiol has become a frequent additive in oral and other healthcare products. Objectives: Our goal was to determine the anti-tumor activity of hinokitiol on human papillomavirus (HPV) positive (n = 3) and negative (n = 2) cell lines derived from cervical or head and neck squamous cell carcinoma (HNSCC) and keratinocyte cell lines (n = 3) transformed spontaneously or with HPV16E6 and E7 oncogenes. Methods: The cell-lines were exposed to hinokitiol at different concentrations (0–200 µM) for 24 h. Cell metabolism, proliferation, and the cell cycle distribution were assessed by MTT- and 3H-thymidine incorporation and flow cytometry. Expressions of p21 and on HPV16E6 and E7 oncogenes were assessed by qPCR. Results: In all carcinoma cell lines, hinokitiol treatment declined the metabolic activity irrespective of the HPV status. This decline was statistically significant, however, only in HPV-positive cell lines CaSki and UD-SCC-2 when exposed to hinokitiol concentrations at 100 and 200 µM, respectively (p < 0.05). Immortalized cell lines, HMK and HPV-positive IHGK, were more sensitive as a similar metabolic effect was achieved at lower hinokitiol concentrations of 3.1, 6.25, and 50 µM, respectively. Hinokitiol blocked DNA synthesis of all carcinoma cell lines without evident association with HPV status. G1 cell cycle arrest and p21 upregulation was found in all cell lines after hinokitiol treatment at higher concentration. However, when the p21 results of all HPV-positive cells were pooled together, the increase in p21 expression was statistically significantly higher in HPV-positive than in HPV-negative cell lines (p = 0.03), but only at the highest hinokitiol concentration (200 µM). In HPV-positive cell lines hinokitiol declined the expression of HPV16E7 and E6 along the increase of p21 expression. The dose-dependent inverse correlation between p21 and E7 was statistically significant in SiHa cells (r = −0.975, p-value = 0.03) and borderline in UD-SCC-2 cells (r = −0.944, p-value = 0.06), in which p21 and E6 were also inversely correlated (r = −0.989). Conclusions: Our results indicate that hinokitiol might have potential in preventing the progress of immortalized cells toward malignancy and the growth of malignant lesions. Hinokitiol can also influence on the progression of HPV-associated lesions by downregulating the E6 and E7 expression.
... Through adjustment in viral particle entry, replication, fusion, viral protein translation and secretion for a lot of viruses, including those involved in respiratory system pathology, zinc has shown a significant impact on viral infections [151,152]. The use of zinc ionophores such as pyrithione and hinokitiol to increase the intracellular Zn concentrations can considerably change the replication rates of picornavirus, which is considered to be the leading cause of common cold [153]. Zinc was previously used against rhinovirus for stopping its replication process in the early 1970 s [154]. ...
Article
Background On 31st December 2019 in Wuhan, China, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was acknowledged. This virus spread quickly throughout the world causing a global pandemic. The World Health Organization declared COVID-19 a pandemic disease on 11th March 2020. Since then, the whole world has come together and have developed several vaccines against this deadly virus. Similarly, several alternative searches for pandemic disease therapeutics are still ongoing. One of them has been identified as nanotechnology. It has demonstrated significant promise for detecting and inhibiting a variety of viruses, including coronaviruses. Several nanoparticles, including gold nanoparticles, silver nanoparticles, quantum dots, carbon dots, graphene oxide nanoparticles, and zinc oxide nanoparticles, have previously demonstrated remarkable antiviral activity against a diverse array of viruses. Objective This review aims to provide a basic and comprehensive overview of COVID-19's initial global outbreak and its mechanism of infiltration into human host cells, as well as the detailed mechanism and inhibitory effects of various nanoparticles against this virus. In addition to nanoparticles, this review focuses on the role of several antiviral drugs used against COVID-19 to date. Conclusion COVID-19 has severely disrupted the social and economic lives of people all over the world. Due to a lack of adequate medical facilities, countries have struggled to maintain control of the situation. Neither a drug nor a vaccine has a 100% efficacy rate. As a result, nanotechnology may be a better therapeutic alternative for this pandemic disease.
... Zn supplementation enhances antiviral, intrinsic, and humoral immunity, and restores the function of immune cells or improves the function of normal immune cells, especially in immunocompromised or elderly patients [82]. Specifically, Zn 2+ was shown to inhibit polyprotein processing in cells infected with human rhinovirus and coxsackievirus B3 [83]. The immune response led by interferons (IFN) and cytotoxic T lymphocytes is invariably required to clear viral infections [82]. ...
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The COVID-19 pandemic, which causes severe respiratory tract infections in humans, has become a global health concern and is spreading rapidly. At present, the most important issue associated with COVID-19 is the immune system and the factors that affect it. It is well known that cow’s milk is highly rich in micronutrients that increase and strengthen the immune system. Research shows that the administration of these nutrients is very effective in fighting COVID-19, and a deficiency in any of them can be a weakness in the fight against the virus. On the other hand, cow’s milk is accessible to the whole population, and drinking colostrum, raw, and micro-filtered milk from cows vaccinated against SARS-CoV-2 could provide individuals with short-term protection against the SARS-CoV-2 infection until vaccines become commercially available. This review aimed to discuss the effects of milk vitamins, minerals, and bioactive peptides on general health in humans to combat viral diseases, especially COVID-19, and to what extent cow’s milk consumption plays a role in providing these metabolites. Cow’s milk contains many bioactive compounds that include vitamins, minerals, biogenic amines, nucleotides, oligosaccharides, organic acids, and immunoglobulins. Humans can meet a significant portion of their requirements for vitamins and minerals through the consumption of cow’s milk. Recent studies have shown that micronutrients such as vitamins D, E, B, C, and A as well as minerals Zn, Cu, Mg, I, and Se and bioactive peptides, each can have positive and significant effects on strengthening the immune system and general health in humans.
... Despite the lack of evidence on the direct effect of zinc ion on SARS-CoV-2, its antiviral effects have been demonstrated in various viral infections (7). As an antiviral nutrient, zinc ion was reported to be able to inhibit replication of rhinoviruses, respiratory syncytial virus (8,9), picornavirus (10), and the RNA polymerase activity of SARS-associated coronavirus and equine arteritis virus (11). Similar to our finding, hypozincemia was reported in paediatric patients with severe pneumonia or Dengue viral infection (12,13). ...
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Zinc ion as an enzyme cofactor exhibits antiviral and anti-inflammatory activity during infection, but circulating zinc ion level during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is unclear. This study aimed to evaluate serum zinc ion level in Coronavirus Disease 2019 (COVID-19) patients and healthy subjects, as well as its correlation with antibodies against SARS-CoV-2. 114 COVID-19 patients and 48 healthy subjects (38 healthy volunteers and 10 close contacts of patients with COVID-19) were included. Zinc ion concentration and levels of antibodies against SARS-CoV-2 Spike 1 + Spike 2 proteins, nucleocapsid protein, and receptor-binding domain in serum were measured. Results showed that the concentration of zinc ion in serum from COVID-19 patients [median: 6.4 nmol/mL (IQR 1.5 – 12.0 nmol/mL)] were significantly lower than that from the healthy subjects [median: 15.0 nmol/mL (IQR 11.9 – 18.8 nmol/mL)] ( p < 0.001) and the difference remained significant after age stratification ( p < 0.001) or when the patients were at the recovery stage ( p < 0.001). Furthermore, COVID-19 patients with more severe hypozincemia showed higher levels of IgG against the receptor-binding domain of SARS-CoV-2 spike protein. Further studies to confirm the effect of zinc supplementation on improving the outcomes of COVID-19, including antibody response against SARS-CoV-2, are warranted.
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Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2Mpro), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc...
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Zinc is an essential trace element that stabilizes protein structures and allosterically modulates a plethora of enzymes, ion channels and neurotransmitter receptors. Labile zinc (Zn²⁺) acts as an intracellular and intercellular signalling molecule in response to various stimuli, which is especially important in the central nervous system. Zincergic neurons, characterized by Zn²⁺ deposits in synaptic vesicles and presynaptic Zn²⁺ release, are found in the cortex, hippocampus, amygdala, olfactory bulb and spinal cord. To provide an overview of synaptic Zn²⁺ and intracellular Zn²⁺ signalling in neurons, the present paper summarizes the fluorescent sensors used to detect Zn²⁺ signals, the cellular mechanisms regulating the generation and buffering of Zn²⁺ signals, as well as the current perspectives on their pleiotropic effects on phosphorylation signalling, synapse formation, synaptic plasticity, as well as sensory and cognitive function.
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Hinokitiol is a natural bio-active tropolone derivative with promising antioxidant and anti-inflammatory properties. This study was conducted to evaluate the ameliorative effects of hinokitiol against acute pancreatitis induced by cerulein. Mice were pre-treated with hinokitiol intraperitoneally for 7 days (50 and 100 mg/kg), and on the final day of study, cerulein (6 × 50 μg/kg) was injected every hour for six times. Six hours after the last dose of cerulein, blood was collected from the mice through retro-orbital plexus for biochemical analysis. After blood collection, mice were euthanized and the pancreas was harvested for studying effects on oxidative stress, pro-inflammatory cytokines, immunohistochemistry and histopathology of tissue sections. Hinokitiol treatment significantly reduced edema of the pancreas and reduced the plasma levels of lipase and amylase in mice with cerulein-induced acute pancreatitis. It also attenuated the oxidative and nitrosative stress related damage as evident from the reduced malondialdehyde (MDA) and nitrite levels, which were significantly increased in the mice with acute pancreatitis. Furthermore, hinokitiol administration significantly reduced the pancreatitis-evoked decrease in the activity of catalase, glutathione (GSH) and superoxide dismutase (SOD) in the pancreatic tissue. Pre-treatment with hinokitiol significantly reduced the elevated levels of pro-inflammatory cytokines like interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) as well as increased the levels of anti-inflammatory cytokine interleukin-10 (IL-10) in the pancreatic tissue of mice with acute pancreatitis. The immunohistochemical expression of nuclear factor kappa light chain enhancer of activated B cells (NF-κB), cyclooxygenase (COX-2) and TNF-α were significantly decreased by hinokitiol in mice with cerulein-induced acute pancreatitis. In conclusion, the results of the present study demonstrate that hinokitiol has significant potential to prevent cerulein-induced acute pancreatitis.
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The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic is currently the major challenge to global public health. Two proteases, papain-like protease (PLpro) and the 3-chymotrypsin-like protease (3CLpro or Mpro), are indispensable for SARS-CoV-2 replication, making them attractive targets for antiviral therapy development. Here we screened a panel of essential metal ions using a proteolytic assay and identified that zinc gluconate, a widely-used zinc supplement, strongly inhibited the proteolytic activities of the two proteases in vitro. Biochemical and crystallographic data reveal that zinc gluconate exhibited the inhibitory function via binding to the protease catalytic site residues. We further show that treatment of zinc gluconate in combination with a small molecule ionophore hinokitiol, could lead to elevated intracellular Zn²⁺ level and thereby significantly impaired the two protease activities in cellulo. Particularly, this approach could also be applied to rescue SARS-CoV-2 infected mammalian cells, indicative of potential application to combat coronavirus infections. Our studies provide the direct experimental evidence that elevated intracellular zinc concentration directly inhibits SARS-CoV-2 replication and suggest the potential benefits to use the zinc supplements for coronavirus disease 2019 (COVID-19) treatment.
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Developing effective strategies to confront coronavirus disease 2019 (COVID-19) has become one of the greatest concerns of the scientific community. In addition to the vast number of global mortalities due to COVID-19, since its outbreak, almost every aspect of human lives has changed one way or another. In the present review, various defensive and offensive strategies developed to confront COVID-19 are illustrated. The Administration of immune-boosting micronutrients/agents, as well as the inhibition of the activity of incompetent gatekeepers, including some host cell receptors (e.g. ACE2) and proteases (e.g. TMPRSS2), are some efficient defensive strategies. Antibody/phage therapies and specifically vaccines also play a prominent role in the enhancement of host defense against COVID-19. Nanotechnology, however, can considerably weaken the virulence of SARS-CoV-2, utilizing fake cellular locks (compounds mimicking cell receptors) to block the viral keys (spike proteins). Generally, two strategies are developed to interfere with the binding of spike proteins to the host cell receptors, either utilizing fake cellular locks to block the viral keys or utilizing fake viral keys to block the cellular locks. Due to their evolutionary conserved nature, viral enzymes, including 3CLpro, PLpro, RdRp, and helicase are highly potential targets for drug repurposing strategy. Thus, various steps of viral replication/transcription can effectively be blocked by their inhibition, leading to the elimination of SARS-CoV-2. Moreover, RNA decoy and CRISPR technologies likely offer the best offensive strategies after viral entry into the host cells, inhibiting the viral replication/assembly in the infected cells and substantially reducing the quantity of viral progeny.
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Background: Since the viruses are intracellular parasite and their replication depends on the host cells, to develop a medication against the viral infections, some substances should be provided having no damage on the host’s cells and tissue. Although the antiviral effects of zinc ion against the viral pathogens has been conspicuous, undesirably it shows a severe toxicity on the cells in cell culture and host tissues in animal models. Methods: To optimize, zinc oxide nanoparticles with antiviral property at the lowest cell toxicity, nano-fibrillar chitosan-ZnO nano-hybrid was synthesized and then, its inhibitory effect against the HSV replication was investigated in comparison to ZnO nanoparticles using plaque reduction and Real time PCR method. Results: Although the infectivity of HSV-1 was reduced in initial steps of virus entry, the significant reduction of viral titer was observed in post exposure of Nano particles on HSV-1 infected cells. In contrary, no changes of viral load were identified in pre-incubation experiment, co-incubation of virus and nanoparticles prior to virus inoculation. Conclusion: Nano-fibrillar CS could dramatically decrease the cell cytotoxicity of ZnO, even though the antiviral effect of ZnO nanoparticles did not change. Nano hybrids appears to penetrate into the host cells and intracellularly inhibits the virus multiplication.
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Rhinoviruses (RVs) are the main cause of recurrent infections with rather mild symptoms characteristic of the common cold. Nevertheless, RVs give rise to enormous numbers of absences from work and school and may become life-threatening in particular settings. Vaccination is jeopardised by the large number of serotypes eliciting only poorly cross-neutralising antibodies. Conversely, antivirals developed over the years failed FDA approval because of a low efficacy and/or side effects. RV species A, B, and C are now included in the fifteen species of the genus Enteroviruses based upon the high similarity of their genome sequences. As a result of their comparably low pathogenicity, RVs have become a handy model for other, more dangerous members of this genus, e.g., poliovirus and enterovirus 71. We provide a short overview of viral proteins that are considered potential drug targets and their corresponding drug candidates. We briefly mention more recently identified cellular enzymes whose inhibition impacts on RVs and comment novel approaches to interfere with infection via aggregation, virus trapping, or preventing viral access to the cell receptor. Finally, we devote a large part of this article to adding the viral RNA genome to the list of potential drug targets by dwelling on its structure, folding, and the still debated way of its exit from the capsid. Finally, we discuss the recent finding that G‑quadruplex stabilising compounds impact on RNA egress possibly via obfuscating the unravelling of stable secondary structural elements.
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Zinc is well‐known to have a central role in human inflammation and immunity and is itself an antiinflammatory and antiviral agent. Despite its massively documented role in such processes, the underlying chemistry of zinc in relation to specific proteins and pathways of the immune system has not received much focus. This short review provides an overview of this topic, with emphasis on the structures of key proteins, zinc coordination chemistry, and probable mechanisms involved in zincbased immunity, with some focus points for future chemical and biological research.
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Background: Coronavirus disease 2019 is caused by exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was reported that Zn ²⁺ is an inhibitor of severe acute respiratory syndrome coronavirus (SARS-CoV). We hypothesize that the same applies to the newly discovered SARS-CoV-2. Material & methods: We compared the structure of RNA-dependent RNA polymerase between SARS-CoV and SARS-CoV-2. The RdRp’s binding to Zn ²⁺ was studied by metal ion-binding site prediction and docking server. Results: Several regions containing key residues were detected. The functional aspartic acid residues RdRp, 618D, 760D and 761D were among the predicted Zn ²⁺ -binding residues. Conclusion: The most probable mechanism of inhibition of RdRp by Zn ²⁺ is binding to the active aspartic acid triad while other binding sites can further destabilize the enzyme or interfere with the fidelity-check mechanism.
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Background: In the midst of the COVID-19 pandemic, there has been an information overload of health data (both accurate and inaccurate) available to the public. With vitamins and supplements being readily accessible, many have turned to using them in an effort to combat the virus. The purpose of this review was to analyse clinical trials regarding vitamins and supplements for the treatment of COVID-19 infections. Methods: Articles were identified through a literature search utilizing online databases and bibliographic review. Results: A total of seven articles were identified for review. All articles evaluated the use of vitamins and supplements for the treatment of COVID-19. Drug therapies included oral vitamin D, intravenous and oral vitamin C, oral vitamin D/magnesium/vitamin B12, oral zinc, oral combination zinc/ascorbic acid, and intravenous alpha-lipoic acid. The end points of each study varied, including the Sequential Organ Failure Assessment score, mortality, rate of intensive care unit (ICU) admissions, negativity of COVID-19 tests, oxygen requirements, and symptom burden. Conclusion: Of the vitamins and supplements that were studied, vitamin D presented the most promising data demonstrating significant decreases in oxygen requirements, need for ICU treatment, SARS-CoV-2 RNA test positivity, and mortality. All of these benefits were exhibited in hospitalized patients. Other vitamins and supplements that were evaluated in studies did not demonstrate any statistically significant benefits. Common shortcomings of the articles included generally small sample sizes, varying sites of study (which could determine the virus variant), a lack of standard of care as background therapy, and utilization of doses that were higher than standard.
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Zinc is an essential trace element that stabilizes protein structures and allosterically modulates a plethora of enzymes, ion channels and neurotransmitter receptors. Labile zinc (Zn 2+) acts as an intracellular and intercellular signalling molecule in response to various stimuli, which is especially important in the central nervous system. Zincergic neurons, characterized by Zn 2+ deposits in synaptic vesicles and presynaptic Zn 2+ release, are found in the cortex, hippocampus, amygdala, olfactory bulb and spinal cord. To provide an overview of synaptic Zn 2+ and intracellular Zn 2+ signalling in neurons, the present paper summarizes the fluorescent sensors used to detect Zn 2+ signals, the cellular mechanisms regulating the generation and buffering of Zn 2+ signals, as well as the current perspectives on their pleio-tropic effects on phosphorylation signalling, synapse formation, synaptic plasticity, as well as sensory and cognitive function.
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The emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed over six million lives globally to date. Despite the availability of vaccines, the pandemic still cannot be fully controlled owing to rapid mutation of the virus that renders enhanced transmissibility and antibody evasion. This is thus an unmet need to develop safe and effective therapeutic options for COVID-19, in particular, remedies that can be used at home. Considering the great success of multi-targeted cocktail therapy for the treatment of viral infections, metal-based drugs might represent a unique and new source of antivirals that resemble a cocktail therapy in terms of their mode of actions. In this review, we first summarize the role that metal ions played in SARS-CoV-2 viral replication and pathogenesis, then highlight the chemistry of metal-based strategies in the fight against SARS-CoV-2 infection, including both metal displacement and chelation based approaches. Finally, we outline a perspective and direction on how to design and develop metal-based antivirals for the fight against the current or future coronavirus pandemic.
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Pyrrolidine dithiocarbamate (PDTC) suppresses NF-B activity and exhibits cytotoxic effects in bovine cerebral endothelial cells (BCECs), and we have previously reported that these PDTC effects were accompanied by an increase in intracellular zinc levels. To further explore the role of zinc in the modulation of NF-B activation, we studied the effect of pyrithione, a zinc ionophore, on NF-B activation in BCECs. Pyri-thione inhibited NF-B activity in a time-and dose-dependent manner. Ca-EDTA, but not Zn-EDTA, prevented pyrithione inhibition of NF-B activity. Pyrithione increased the intracellular zinc level within 15 min. This effect was also abolished by Ca-EDTA, but not by Zn-EDTA. The potency of pyrithione on NF-B inhibition and zinc influx was approximately one order of magnitude more potent than PDTC. These findings establish the regulatory role of intracellular zinc levels on NF-B activity in BCECs.
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Mammalian eukaryotic translation initiation factor 4F (eIF4F) is a cap-binding protein complex consisting of three subunits: eIF4E, eIF4A, and eIF4G. In yeast and plants, two related eIF4G species are encoded by two different genes. To date, however, only one functional eIF4G polypeptide, referred to here as eIF4GI, has been identified in mammals. Here we describe the discovery and functional characterization of a closely related homolog, referred to as eIF4GII. eIF4GI and eIF4GII share 46% identity at the amino acid level and possess an overall similarity of 56%. The homology is particularly high in certain regions of the central and carboxy portions, while the amino-terminal regions are more divergent. Far-Western analysis and coimmunoprecipitation experiments were used to demonstrate that eIF4GII directly interacts with eIF4E, eIF4A, and eIF3. eIF4GII, like eIF4GI, is also cleaved upon picornavirus infection. eIF4GII restores cap-dependent translation in a reticulocyte lysate which had been pretreated with rhinovirus 2A to cleave endogenous eIF4G. Finally, eIF4GII exists as a complex with eIF4E in HeLa cells, because eIF4GII and eIF4E can be purified together by cap affinity chromatography. Taken together, our findings indicate that eIF4GII is a functional homolog of eIF4GI. These results may have important implications for the understanding of the mechanism of shutoff of host protein synthesis following picornavirus infection.
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Eukaryotic protein synthesis initiation factor (eIF) 4 gamma, also known as p220, is a component of the protein complex eIF-4, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome. Peptide sequence data from rabbit reticulocyte eIF-4 gamma was used to synthesize oligonucleotide probes and polymerase chain reaction primers. These were used to screen lambda-cDNA libraries from rabbit and human brain, yielding a partial rabbit and a complete human cDNA sequence of 5.1 kilobases. Northern blot and primer extension analysis indicated that the cDNA sequence was complete. To confirm that the cDNA represented that of eIF-4 gamma, three peptides were synthesized based on cDNA sequences and used to produce anti-peptide antibodies. The antibodies specifically recognized intact eIF-4 gamma and its cleavage products following poliovirus infection. The eIF-4 gamma mRNA contains AUG codons at nucleotides 6, 67, 90, 165, and 369, but only the last is followed by a long open reading frame. The eIF-4 gamma polypeptide is 154 kDa (1396 amino acid residues) and contains sequence motifs of potential interest: a sequence (AGLGPR) that is similar to the substrate recognition sequence of protease 2A from rhinovirus serotype 14, five PEST regions with scores greater than 10, which are characteristic of rapidly degraded proteins, stretches of polyglutamic acid, and numerous potential phosphorylation sites.
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Use has been made of a monoclonal antibody (designated 8F5) to map a neutralizing epitope on the viral capsid protein VP2 of human rhinovirus 2 (HRV2). This antibody which was raised against the native virus, neutralizes HRV2 and is also capable of recognizing denatured VP2 on Western blots. To examine the binding site of 8F5, VP2 of HRV2 was expressed in Escherichia coli. Deletions starting at the 3' end were then introduced into the gene for VP2 using Bal-31 nuclease. Polypeptides shortened at the carboxy terminus of VP2 were obtained from the deletions and were blotted onto nitrocellulose. The samples were then probed with monoclonal antibody 8F5. Recognition by 8F5 was maintained as long as the expressed polypeptide contained the VP2 sequence up to amino acid 164 or beyond. However, when the VP2 sequence was truncated to amino acid 153 or less 8F5 was no longer able to bind. The neutralization epitope (or part of it) recognized by 8F5 on VP2 is therefore located between amino acids 153 and 164.
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Following poliovirus infection of HeLa cells, the synthesis of cellular proteins is inhibited but translation of poliovirus mRNA proceeds. The defect in the recognition of host cell mRNA may be due to a change in a cap recognition complex which, when added to an infected cell lysate, restores the ability to translate capped mRNAs. We employed immunoblotting techniques to examine initiation factors in crude lysates from uninfected and poliovirus-infected HeLa cells. Using an antiserum against eucaryotic initiation factor 3, we detected an antigen of approximate molecular weight 220,000 in uninfected cell lysates but not in infected cell lysates. Antigenically related polypeptides of 100,000 to 130,000 daltons, presumably degradation products, were detected in the infected cell lysate. The time course for degradation of the 220,000-dalton polypeptide correlates with that for inhibition of cellular protein synthesis in vivo. A portion of the population of 220,000-dalton polypeptides apparently associates with initiation factor eIF3 but is readily dissociated in buffers containing high salt. Affinity-purified antibodies against the polypeptide recognize a protein of the same size in a purified preparation of a cap binding protein complex obtained by cap-affinity chromatography. We postulate that the 220,000-dalton polypeptide is an essential component of the cap recognition complex and that its degradation in poliovirus-infected cells results in the inhibition of host cell translation. These results are in the first demonstration of a specific structural defect in an initiation factor resulting from poliovirus infection.
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Hinokitiol (I) and tropolone (II) showed characteristic cytotoxic effects in vitro on five kinds of human and murine cell lines and blastic lymphocytes from mouse splenocytes. The cytotoxic effect of I on the growth of murine and human tumor cell lines, including RL male-1, MH134, HL60, K562 and KATO-III was definite when examined by thymidine incorporation into DNA and its 50% inhibitory concentration (IC50) on all cells was 0.3-0.6 microgram/ml. Compound II also showed comparable cytotoxic effects on these cell lines, indicating a little lower activity when compared to I. Furthermore, I and II also completely suppressed the [3H]thymidine ([3H]TdR) incorporation of mitogen-induced blastic lymphocytes. The suppressive activity on mouse lymphocyte proliferative response to concanavaline-A was also found with both compounds at a low concentration of 0.32 microgram/ml. As compound I is known to be of fairly low toxicity (LD50: 453 + 24 mg/kg in mice), the antitumor and immuno-suppressive effect of hinokitiol (I) should be further investigated.
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We used the ratioable fluorescent dye mag-fura-5 to measure intracellular free Zn2+ ([Zn2+]i) in cultured neocortical neurons exposed to neurotoxic concentrations of Zn2+ in concert with depolarization or glutamate receptor activation and identified four routes of Zn2+ entry. Neurons exposed to extracellular Zn2+ plus high K+ responded with a peak cell body signal corresponding to a [Zn2+]i of 35-45 nM. This increase in [Zn2+]i was attenuated by concurrent addition of Gd3+, verapamil, omega-conotoxin GVIA, or nimodipine, consistent with Zn2+ entry through voltage-gated Ca2+channels. Furthermore, under conditions favoring reverse operation of the Na+-Ca2+ exchanger, Zn2+ application induced a slow increase in [Zn2+]i and outward whole-cell current sensitive to benzamil-amiloride. Thus, a second route of Zn2+ entry into neurons may be via transporter-mediated exchange with intracellular Na+. Both NMDA and kainate also induced rapid increases in neuronal [Zn2+]i. The NMDA-induced increase was only partly sensitive to Gd3+ or to removal of extracellular Na+, consistent with a third route of entry directly through NMDA receptor-gated channels. The kainate-induced increase was highly sensitive to Gd3+ or Na+ removal in most neurons but insensitive in a minority subpopulation ("cobalt-positive cells"), suggesting that a fourth route of neuronal Zn2+ entry is through the Ca2+-permeable channels gated by certain subtypes of AMPA or kainate receptors.
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Human rhinoviruses (HRVs) are the predominant cause of the common cold. The frequency of HRV infections in industrial countries and the lack of effective therapeutical treatment underline the importance of research for new antiviral substances. As viral infections are often accompanied by the generation of oxidative stress inside the infected cells, several redox-active substances were tested as potential antivirals. In the course of these studies it was discovered that pyrrolidine dithiocarbamate (PDTC) is an extremely potent compound against HRV and poliovirus infection in cell culture. Besides the ability to dramatically reduce HRV production by interfering with viral protein expression, PDTC promotes cell survival and abolishes cytopathic effects in infected cells. PDTC also protects cells against poliovirus infection. These effects were highly specific, as several other antioxidants (vitamin C, Trolox, 2-mercaptoethanol, and N-acetyl-l-cysteine) are inactive against HRV infection. Synthesis of HRV proteins and cleavage of eucaryotic initiation factor 4G responsible for host cell shutoff of cellular protein synthesis are severely inhibited in the presence of PDTC.
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A novel cationic fluorescent zinc (Zn2+) indicator (RhodZin-3) with nanomolar affinity for Zn2+ has been synthesized. RhodZin-3 exhibits large pH-independent fluorescence increases in the orange region of the visible wavelength spectrum with increasing zinc concentrations, and no sensitivity to physiologically relevant Ca2+ concentrations. Experiments in neuronal cell cultures show that RhodZin-3 effectively localizes into mitochondria and detects changes of intramitochondrial free Zn2+ ([Zn2+]m).
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The ability of the 3A protein of coxsackievirus B (CVB) to inhibit protein secretion was investigated for this study. Here we show that the ectopic expression of CVB 3A blocked the transport of both the glycoprotein of vesicular stomatitis virus, a membrane-bound secretory marker, and the alpha-1 protease inhibitor, a luminal secretory protein, at a step between the endoplasmic reticulum (ER) and the Golgi complex. CVB 3A contains a conserved proline-rich region in its N terminus. The importance of this proline-rich region was investigated by introducing Pro-to-Ala substitutions. The mutation of Pro19 completely abolished the ability of 3A to inhibit ER-to-Golgi transport. The mutation of Pro14, Pro17, or Pro20 also impaired this ability, but to a lesser extent. The mutation of Pro18 had no effect. We also investigated the possible importance of this proline-rich region for the function of 3A in viral RNA replication. To this end, we introduced the Pro-to-Ala mutations into an infectious cDNA clone of CVB3. The transfection of cells with in vitro-transcribed RNAs of these clones gave rise to mutant viruses that replicated with wild-type characteristics. We concluded that the proline-rich region in CVB 3A is required for its ability to inhibit ER-to-Golgi transport, but not for its function in viral RNA replication. The functional relevance of the proline-rich region is discussed in light of the proposed structural model of 3A.
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