Protease Inhibitors - Science topic

Penicillium sp. (IBWF 040‐09) produces a protease inhibitor that can potentially be used against the main protease of human African trypanosomiasis. Since the target substance is formed intracellularly (under nutrient limitation), the fungal pellet is preferred compared to the free mycelia in bioreactor cultivation. The optimization of the producti...

Human transmembrane serine protease 2 (TMPRSS2) has garnered substantial interest due to its clinical significance in various pathologies, notably its pivotal role in viral entry into host cells. The development of effective strategies to target TMPRSS2 is a current area of intense research and necessitates a consistent source of active TMPRSS2 wit...

Background: Cystatins, encoded by the CST gene family, are a superfamily of cysteine protease inhibitors involved in a wide array of biological functions, including immune modulation and antimicrobial defense. Cystatin proteins are implicated in tumor progression through multiple mechanisms. However, their roles in bladder cancer remain poorly unde...

Purpose To elicit the signs and/or symptoms, and impacts on daily living experienced by patients with alpha-1 antitrypsin deficiency-associated liver disease (AATD-LD). Methods A preliminary “concept list” of signs and/or symptoms, and impacts was developed from a targeted literature review, patient blog posts, and clinician interviews. Subsequent...

Background Trichinosis is one of the most widespread parasitic infections worldwide. Trichinella spiralis not only infects humans but can also utilize wild anddomestic animals as hosts. The serine protease inhibitors secreted by Trichinella spiralis play a critical role in its invasion and immune evasion. Serpins can effectively inhibit host protea...

Counteracting plant RNA silencing ensures successful viral infection. The P25 protein encoded by potato virus X (PVX) is a multifunctional protein that acts as a viral RNA silencing suppressor (VSR). In this study, we screened out a potato type I protease inhibitor (PI) in Nicotiana benthamiana (NbPI) that interacts with P25. Silencing of NbPI by t...

Lung manifestations of chronic obstructive pulmonary disease (COPD) are often exacerbated by influenza A virus infections; however, the underlying mechanisms remain largely unknown, and hence therapeutic options are limited. Using a physiologically relevant human lung airway-on-a-chip (Airway Chip) microfluidic culture model lined with human airway...

The research examined alterations in DNA methylation patterns of leukocytes among women who experienced early pregnancy loss and displayed a significant pro-inflammatory immune reaction. The findings suggested that an intensified pro-inflammatory response during the initial phases of pregnancy, when genital infections are absent and the corrective...

Nirmatrelvir, the active compound of the drug Paxlovid, inhibits the Main protease of SARS-CoV-2 (MPro, 3CLPro, NSP5). Its therapeutic application reduces but does not abolish the progression of COVID-19 in humans. Here we report a strong synergy of Nirmatrelvir with inhibitors of the ER chaperone GRP78 (HSPA5, BiP). Combining Nirmatrelvir with the...

Proteases rely on their active sites for substrate specificity, but these sites have inherent limitations that impact enzymatic efficiency and regulation. Exosites and cofactors help overcome these constraints by enhancing the protease's substrate interactions, specificity, and inhibition. Recent research by Gangemi et al. highlights the role of ex...

We describe a method tailored to the in-cell selection of protease inhibitors. In this method, a target protease is co-expressed with a selective substrate, the product of which kills host cells. Therefore, the method can be applied to identify potential inhibitors based on cell host survival when inhibition of the target protease occurs. The TEV p...

Molecular optimization is a crucial yet complex and time-intensive process that often acts as a bottleneck for drug development. Traditional methods rely heavily on trial and error, making multi-objective optimization both time-consuming and resource-intensive. Current AI-based methods have shown limited success in handling multi-objective optimiza...

Fusarium verticillioides isolated from soil was found to produce extracellular cutinase under optimized culture conditions. The enzyme was purified using ion‐exchange and size‐exclusion chromatography, achieving a purification fold of 12.5 and a final yield of 62%. The molecular weight of the purified cutinase was determined to be 25 kDa using SDS‐...

Chronic obstructive pulmonary disease (COPD) is a global health problem due to its high death and morbidity worldwide, which is characterized by an incompletely reversible limitation in airflow that is not fully reversible. Unfortunately, Western medical treatments are unable to reverse the progressive decline in lung function. Importantly, polyphe...

A library of known aspartic protease inhibitors was screened to identify compounds that inhibit plasmepsin V from Plasmodium vivax. This screen revealed compounds with an imino‐pyrimidinone‐fused pyrrolidine (IPF) scaffold that exhibited sub‐micromolar inhibitory activity against plasmepsin V. Further screening of IPF analogs against the related as...

Proteases play a pivotal role in cancer progression, facilitating processes such as extracellular matrix degradation, angiogenesis, and metastasis. Consequently, protease inhibitors have emerged as promising therapeutic agents in oncology. This review provides a comprehensive overview of the mechanisms by which protease inhibitors modulate cancer b...

The coexistence of HIV and sickle cell disease (SCD) presents unique clinical challenges due to overlapping pathophysiological mechanisms, including chronic inflammation, immune dysregulation, and endothelial dysfunction. While antiretroviral therapy (ART) has significantly improved survival and quality of life in HIV-infected individuals, its impa...

Using environment-friendly, effective, and stable protein molecules that can prevent or affect the metabolism of the pest Helicoverpa armigera could be an effective way to control this pest. Protease inhibitors (PIs) are distributed in the different parts of the plants like seeds and leaves. The protease inhibitors are low molecular weight proteins...

Nephrin is an essential constituent of the slit diaphragm of the kidney filtering unit. Loss of nephrin expression leads to protein leakage into the urine, one of the hallmarks of kidney damage. Autoantibodies against nephrin have been reported in patients with minimal change disease and recurrent focal segmental glomerulosclerosis. Understanding t...

The objective of this investigation was to synthesize spirothiazolidinone-chalcone derivatives and evaluate them for anti-inflammatory action. Five 4-substituted benzaldehydes were utilized for the aldol condensation leading to chalcones of spirothiazolidinone. The compounds were obtained in yield of 64-72% and displayed varying solubility with all...

Chemosensory protein 16 was identified in the hemolymph of Galleria mellonella as a protein with an amount increasing after oral infection with 10^3 CFU of Pseudomonas entomophila, and decreasing after infection with a higher dose (10^5 CFU) of bacteria. The expression of the CSP16 gene occurred in the fat body and in the gut and correlated with ch...

Enterovirus 71 (EV-71) is a major causative agent of hand, foot, and mouth disease (HFMD), which mainly affects infants and children. However, there are no effective clinical drugs for the treatment of HFMD. The 3C protease (3Cpro) is an ideal drug target for antivirals, as this enzyme plays an indispensable role in virus replication. Considering t...

Matrix metalloproteinases (MMPs) are a family of proteases that drive degradation of extracellular matrix (ECM) across many tissues. MMP activity is antagonized by tissue inhibitors of metalloproteinases (TIMPs), resulting in a complex multivariate system with many MMP isoforms and TIMP isoforms interacting across a network of biochemical reactions...

With the goal of accelerating the discovery of small molecule-protein complexes, we leverage fast, low-dose, event based electron counting microcrystal electron diffraction (MicroED) data collection and native mass spectrometry. This approach resolves structures of the epoxide-based cysteine protease inhibitor, and natural product, E-64, and its bi...

Despite the passage of approximately five years since the outbreak, an efficacious remedy for SARS-CoV-2 remains elusive, highlighting the urgent imperative for developing SARS-CoV-2 potent inhibitors. In our current study, we have unmasked the hitherto unrealized potential of dihydropyrimidine-2-thiones against the Main Protease (Mpro) of SARS-CoV...

Tea polyphenols, the primary bioactive constituents responsible for the various health benefits of tea, can be categorized into different subgroups according to their structural characteristics. However, the distinctions in antiviral activity among the diverse types of polyphenolic compounds remain unexplored. In the present study, fifty-eight tea...

Cardiovascular involvement in patients with human immune deficiency (HIV) has gained significant attention as the improved life expectancy of individuals with HIV has changed the paradigm regarding the long-term impact of the virus on cardiovascular health. We reviewed current literature on the prevalence, diagnosis, and unique characteristics of c...

It was found that the serine protease inhibitors BmSPI38 and BmSPI39 in silkworm can strongly inhibit the activity of porcine pancreatic elastase, which has potential applicational value in the drug research and development of lung diseases, inflammatory diseases, and skin aging caused by the excessive release of elastase. Previous studies have sho...

TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and in respiratory virus cell entry. To date, no inhibitors have been specifically developed for this protease. In this study, a chemical library of 65 ketobenzothiazole-based peptidomimetic molecules was screened against a proteolytica...

Zika virus transmitted by mosquito, has emerged as a significant public health threat with the potential to cause global pandemics. This study explores natural phytochemicals as potential inhibitors of Zika virus (ZIKV) infection by targeting the essential NS2B-NS3 protease complex, which plays a crucial role in viral replication. A virtual screeni...

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, able to thrive in a challenging tumor microenvironment. Current standard therapies, including surgery, radiation, chemotherapy, and chemoradiation, have shown a dismal survival prognosis, resulting in less than a year of life in the metastatic setting. Methods: The pressin...

Background: Proteolytic cleavage of inactive pathogen proteins by furin is critical for their entry into human cells, and thus furin cleavage of the SARS-CoV-2 spike protein was identified as a prerequisite for virus binding and the subsequent infection of human cells in the recent COVID-19 pandemic. We report a water-aware structure-based protease...

Cysteine proteases are essential for the survival of Leishmania parasites that cause several clinical forms of leishmaniases. Inhibiting cysteine protease can be a promising strategy against parasitic diseases because of their essential functions in the life cycles of these pathogens. The aim of the present study was to synthesize and evaluate pept...

Oral administration of biologic drugs is challenging because of the degradative activity of the upper gastrointestinal tract. Strategies that use engineered microbes to produce biologics in the lower gastrointestinal tract are limited by competition with resident commensal bacteria. Here we demonstrate the engineering of bacteriophage (phage) that...

Cydia pomonella (L.) (Lepidoptera: Tortricidae) is one of the significant pests of apples that causes irreparable damage to apple orchards every year. This study investigates the digestive enzyme profile of codling moth and assesses effectiveness of some metal ions and protease inhibitors on their activity. After rearing insects in the laboratory c...

Secondary Immunodeficiency Disorders (SID) such as HIV had claimed to have taken approximately 42.3 million lives. SIDs are defined as a transient or persistent impairment of the function of cells or tissues of the immune system, due to multiple external factors including underlying infections such as HIV, specific medications and medical condition...

Human immunodeficiency virus (HIV) is a serious public health that has been managed by different HAART regimen for people infected to live a healthier live and also reduce the risk of HIV transmission. But this has come without its undesirable effects which may last only a few days or weeks or that may not appear for months or years after starting...

The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents the systematic design of quinoline-containing SARS-CoV-2 papain-like protease (PLpro) inhibitors as potential oral antiviral drug candidates. By leveraging the recently discovered Val70Ub binding site in PLpro, we designed a series o...

Antiretroviral therapy (ART) has significantly improved the life expectancy of people living with HIV-1 (PLWH). However, prolonged ART use is linked to metabolic alterations and oxidative stress. The paraoxonase (PON) enzymes, especially PON-1 and PON-2, are critical in maintaining antioxidant balance. Their activity can be influenced by polymorphi...

The serine protease prostasin on the surface of the exosomes released from epithelial cells can interact with ectopically over-expressed cell-surface serine protease matriptase in cancerous B cells to initiate the prostasin–matriptase proteolytic activation cascade. Matriptase activation and the ensuing self-activation result in its removal from ca...

Coronavirus disease 2019 (COVID‐19) is a systemic infection frequently involving the haematopoietic system. Thrombocytopenia is associated with increased risks of severe disease progression and mortality. Antiviral agents have shown much promise in decreasing viral load and shortening the time to the resolution of symptoms. However, their effect on...

The main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as 3CLpro, is crucial in the virus’s life cycle and plays a pivotal role in COVID-19. Understanding how small molecules inhibit 3CLpro’s activity is vital for developing anti-COVID-19 therapeutics. To this end, we employed Gaussian accelerated molecular dyn...

Respiratory viral infections present significant global health challenges, causing substantial morbidity and mortality, particularly among highly susceptible components of the population. The emergence of pandemics and epidemics, such as those caused by influenza viruses and coronaviruses, emphasizes the urgent need for effective antiviral therapeu...

Background There are limited data on how historical nucleoside reverse transcriptase inhibitor (NRTI) resistance-associated mutations (RAMs) other than M184V/I, affect the activity of B/F/TAF. We evaluated the outcomes of switching virologically suppressed (HIV-1 RNA < 50 copies/mL) individuals harbouring major RAMs from boosted protease inhibitor...

Macrophages play a multifaceted role in mounting an immune response against pathogens through phagocytosis, antigen presentation, and cytokine production. Activated macrophages are critical for the initiation, maintenance, and resolution of inflammation. They can either be classically activated (Th1 response), which promotes inflammation, or altern...

Cancer management has traditionally depended on chemotherapy as the mainstay of treatment; however, recent advancements in targeted therapies and immunotherapies have offered new options. Ubiquitin-specific proteases (USPs) have emerged as promising therapeutic targets in cancer treatment due to their crucial roles in regulating protein homeostasis...

Understanding plant-insect interactions can help control the harm of herbivorous pests. According to transcriptome data, transcripts of Solanum lycopersicum responding to feeding by Tuta absoluta were screened for important endopeptidase inhibitors. These genes were annotated as serine-type endopeptidase inhibitors from the potato inhibitor I famil...

Background An N-terminal octapeptide cleavage of the cystatin C protein was discovered by mass spectrometry when cerebrospinal fluid (CSF) was stored at –20°C for 3 months, which did not occur when CSF was stored at –80°C. Objective The aim was to develop an immunoassay as quality assessment tool to detect this –20°C cleavage of cystatin C in CSF...

Background The emergence of drug‐resistant mutations in human immunodeficiency virus (HIV) over time presents a challenge to treatment. We describe the development of drug‐resistance mutations and ART efficacy reduction in Vietnamese patients with failure of first‐line ART during a 5‐year period. Methods This is a 5‐year observational cohort study...

Purpose Hypertonic stress can induce apoptosis, inflammation, and dry eye disease (DED) through the upregulation of HMGB1 expression. However, its role in mediating and maintaining lysosomal homeostasis and suppressing DED development in living and in vitro models is unclear. Methods Immunofluorescence, nucleoplasmic separation, and electron micro...

Background: SERPINB5, also known as Maspin, is a non-inhibitory member of the serine protease inhibitor superfamily. SERPINB5 exerts diverse effects on a variety of human cancers, including cell proliferation, angiogenesis, apoptosis, tumor invasion, and metastasis. SERPINB5 has traditionally been regarded as a tumor suppressor gene, but emerging e...

Targeting the tumor microenvironment (TME) is an attractive strategy for developing new drugs with anticancer activity against triple-negative breast cancer (TNBC). Interleukins (ILs) are key players in the TME cytokine network promoting cancer progression. Recent studies have highlighted the involvement of IL-20 receptor subunit alpha (IL-20RA) si...

Coronavirus disease 2019, which leads to pneumonia, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAY1216 is a 3C-like protease inhibitor that targets SARS-CoV-2. The aim of our study was to assess the pharmacokinetics (PK) and safety of RAY1216 in healthy volunteers. This was a randomized, placebo-controlled, double-bl...

HIV drug resistance (HIVDR) presents a significant challenge to antiretroviral therapy (ART) success, particularly in resource-limited settings like Ethiopia. This cross-sectional study investigated viral suppression rates and resistance patterns among patients on second-line ART across 28 Ethiopian health facilities. Blood samples collected from 5...

The main burden in treating human immunodeficiency virus (HIV) infection currently, is the side effects of the antiretroviral therapy (ART) used, because each treatment is toxic to the liver. This study uses optimal control theory applied to a mathematical model that describes the dynamics of HIV infection in the liver. The optimal controls are pre...

Human norovirus (HuNoV) is a leading cause of gastroenteritis worldwide and is associated with significant morbidity, mortality, and economic impact. There are currently no licensed antiviral drugs for the treatment of HuNoV-associated gastroenteritis. The HuNoV protease plays a critical role in the initiation of virus replication by cleaving the p...

In the last few years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the cause of a worldwide pandemic, highlighting the need for novel antiviral agents. The main protease (Mpro) of SARS-CoV-2 was immediately identified as a crucial enzyme for viral replication and has been validated as a drug target. Here, we present the de...

Whipworms (Trichuris spp) are ubiquitous parasites of humans and domestic and wild mammals that cause chronic disease, considerably impacting human and animal health. Egg hatching is a critical phase in the whipworm life cycle that marks the initiation of infection, with newly hatched larvae rapidly migrating to and invading host intestinal epithel...

The process of viral entry into host cells is crucial for the establishment of infection and the determination of viral pathogenicity. A comprehensive understanding of entry pathways is fundamental for the development of novel therapeutic strategies. Standard techniques for investigating viral entry include confocal microscopy and flow cytometry, b...

Purpose Cystatin 2 (CST2) is a cysteine protease inhibitor, and recent research suggests its potential involvement in cancer development. However, its role in the occurrence, progression, and prognosis of pan-cancer has not been systematically investigated. Materials and methods This study comprehensively analyzes the differential expression of CS...

The treatment landscape for hepatitis C virus (HCV) infection has transformed over the past few decades, evolving from the limited efficacy of interferon (IFN) monotherapy to the highly successful pan-genotypic direct-acting antivirals (DAAs) used today. Initially, alpha-interferon monotherapy, introduced in the 1990s, was the standard treatment, y...

Canine distemper is a severe and lethal viral disease of dogs and wild carnivores with an urgent need for the identification of effective antiviral agents against canine distemper virus (CDV). We assessed multiple agents for their ability to block the replication of three different lineages of CDV isolated from wild carnivores in the United States....

The COVID-19 pandemic, driven by the novel coronavirus SARS-CoV-2, has drastically reshaped global health and socioeconomic landscapes. The papain-like protease (PLpro) plays a critical role in viral polyprotein cleavage and immune evasion, making it a prime target for therapeutic intervention. Numerous compounds have been identified as inhibitors...

Dengue is one of the most prevalent viruses transmitted by the Aedes aegypti mosquitoes. Currently, no specific medication is available to treat dengue diseases. The NS2B–NS3 protease is vital during post-translational processing, which is a key target in this study. Due to methoxy group substitution, methoxyflavones are more bioavailable and metab...

Background Ensitrelvir is a novel SARS-CoV-2 3-chymotrypsin-like protease inhibitor, similar to nirmatrelvir/ritonavir. Several case reports have demonstrated the efficacy of 3-chymotrypsin-like protease inhibitors in treating prolonged coronavirus disease 2019 (COVID-19) in immunocompromised patients. Tacrolimus (TAC) is a widely used immunosuppre...

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a major challenge to global health. Targeting the main protease of the virus (Mpro), which is essential for viral replication and transcription, offers a promising approach for therapeutic intervention. In this study, advanced computational techniques such as molecular docking and molecul...

Background: in the twenty-first century, the emergence of COVID-19 as a highly transmissible pandemic disease caused by SARS-CoV-2 posed a significant threat to humanity. Aims & Objectives: the disease spreads through small respiratory droplets, necessitating the use of various compounds for treatment, with alkaloids being recognized as particularl...

Constrained peptides possess excellent properties for identifying lead compounds in drug discovery. While it has become increasingly straightforward to discover selective high‐affinity peptide ligands, especially through genetically encoded libraries, their stability and bioavailability remain significant challenges. By integrating macrocyclization...

Background The pathophysiology of polyuria and polydipsia secondary to exogenous glucocorticoid excess is incompletely understood. Objective Investigate plasma AVP (pAVP) and serum CoP (sCoP) concentrations in healthy dogs before, during, and after abrupt discontinuation of a long‐term course of orally administered prednisolone. Animals Eight hea...

Nucleolin (NCL) is a prevalent and widely distributed nucleolar protein in cells. While primarily located in the nucleolus, NCL is also found within the nucleoplasm, cytoplasm, and even on the cell surface. NCL’s unique nature arises from its multifaceted roles and extensive interactions with various proteins. The structural stability of NCL is rel...

Tick-borne encephalitis virus (TBEV) is flavivirus transmitted to the host via tick saliva which contains various molecules with biological impacts. One of such molecules is Iristatin, a cysteine protease inhibitor from Ixodes ricinus that has been shown to have immunomodulatory properties. To characterize Iristatin in the relation to TBEV, we inve...

RA-0002034 ( 1 ) is a potent covalent inhibitor targeting the alphavirus nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of 1 were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione S -transferase (GST)-catalyzed conjugat...

Background Drug repurposing has become a widely adopted strategy to minimise research time, costs, and associated risks. Combinations of protease inhibitors such as lopinavir and darunavir with ritonavir have been repurposed as treatments for COVID-19. Although lopinavir-ritonavir (LPV/r) and darunavir-ritonavir (DRV/r) have shown in vitro efficacy...

Millet grains are well known for their nutritional benefits but availability of antinutritional factors in these grains impair nutrient absorption and utilization. This review explores various antinutritional factors present in millets, such as tannins, phytic acid, protease inhibitors, and trypsin inhibitors, and their impact on human health. Addi...

Due to the increased burden of non‐AIDS‐related comorbidities in people living with HIV (PLHIV), identifying biomarkers and mechanisms underlying premature aging and the risk of developing age‐related comorbidities is a priority. Evidence suggests that the plasma proteome is an accurate source for measuring biological age and predicting age‐related...

Human pluripotent stem cells (hPSCs) can be differentiated in vitro to an increasing number of mature cell types, presenting significant promise for addressing a wide range of diseases and studying human development. One approach to further enhance stem cell differentiation methods would be to coordinate multiple inducible gene or protein switches...