Article

Synthesis of Highly Efficient Multivalent Disaccharide/[60]Fullerene Nanoballs for Emergent Viruses

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Abstract

After the last epidemic of Zika virus (ZIKV) in Brazil that peacked in 2016, it has been demonstrated growing evidence of the link between this teratogenic flavivirus and microcephaly cases. However, no vaccine or antiviral drug has been yet approved. ZIKV and Dengue virus (DENV) entry to the host cell takes place through several receptors including DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin), so that the blockade of this recep-tor through multivalent glycoconjugates supposes a promising biological target to inhibit the infection process. In order to get enhanced multivalency in biocompatible systems, tridecafullerenes appended with up to 360 1,2-mannobiosides have been synthesized using a strain promoted cycloaddition of azides to alkynes (SPAAC) strategy. These systems have been tested against ZIKV and DENV infection, showing an outstanding activity in the picomolar range.

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... 1,42,44 However, its tetrameric structure remains unknown, making it difficult to develop novel glycoconjugates that can potently and specifically target DC-SIGN for therapeutic interventions, especially when the overlapping glycan specificity of various lectins is considered. 1 Using the QD-glycans, we have found that DC-SIGN's 4 CRDs bind simultaneously to one QD and give an impressive affinity enhancement factor (β) of up to 1.5 million fold over the corresponding monovalent binding. The QD-glycans also potently inhibit DC-SIGN-mediated augmentation of Ebola virus entry into host cells with sub-nM IC 50 values. 35 Despite such success, the cytotoxicity and long-term toxicity of the CdSe QD scaffold has significantly limited its potential use as DC-SIGN targeting therapeutic agents, especially under in vivo conditions. ...
... 34 Moreover, glycoconjugates with higher glycan valency have often shown to exhibit better virus inhibition potencies. 9,14,16,21,50 Thus, we are interested to study whether GNP-glycans' DC-SIGN/R binding affinity and virus inhibition potency can be further enhanced by increasing its surface glycan density. Thus, a branched version of the DHLA-glycan ligand, each containing three terminal glycans, are also synthesized (denoted as DHLA-(Man) 3 or DHLA-(DiMan) 3 , respectively). ...
... Thus, a branched version of the DHLA-glycan ligand, each containing three terminal glycans, are also synthesized (denoted as DHLA-(Man) 3 or DHLA-(DiMan) 3 , respectively). 50 The branched ligands have the same DHLA anchoring group for GNP binding as the monomeric glycans. Thus, a similar number of ligands are expected to coat each GNP, allowing us to prepare more densely glycosylated GNPs as shown schematically in Figure 1. ...
Article
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Multivalent lectin-glycan interactions are widespread in biology and are often exploited by pathogens to bind and infect host cells. Glycoconjugates can block such interactions and thereby prevent infection. The inhibition potency strongly de-pends on matching the spatial arrangement between the multivalent binding partners. However, the structural details of some key lectins remain unknown and different lectins may exhibit overlapping glycan specificity. This makes it difficult to design a glycoconjugate that can potently and specifically target a particular multimeric lectin for therapeutic interventions, especially under the challenging in vivo conditions. Conventional techniques such as surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) can provide quantitative binding thermodynamics and kinetics. However, they cannot reveal key structural information, e.g. lectin's binding site orientation, binding mode, and inter-binding site spacing, which are critical to design specific multivalent inhibitors. Herein we report that gold nanoparticles (GNPs) displaying a dense layer of simple glycans are powerful mechanistic probes for multivalent lectin-glycan interactions. They can not only quantify the GNP-glycan-lectin binding affinities via a new fluorescence quenching method, but also reveal drastically different affinity enhancing mechanisms between two closely-related tetrameric lectins, DC-SIGN (simultaneous binding to one GNP) and DC-SIGNR (inter-crosslinking with multiple GNPs), via a combined hydrodynamic size and electron microscopy analysis. Moreover, a new term, potential of assembly formation (PAF) has been proposed to successfully predict the assembly out-comes based on the binding mode between GNP-glycans and lectins. Finally, the GNP-glycans can potently and completely inhibit DC-SIGN-mediated augmentation of Ebola virus glycoprotein-driven cell entry (with IC50 values down to 95 pM), but only partially block DC-SIGNR-mediated virus infection. Our results suggest that the ability of a glycoconjugate to simulta-neously block all binding sites of a target lectin is key to robust inhibition of viral infection.
... [5][6][7][8][9] In the thirty years since C 60 was obtained in macroscopic quantities for the first time, [10] synthetic organic chemists have come up with countless methodologies to functionalize fullerenes. [11] In this regard, the double bonds found at the junctions between the sixmembered rings of fullerene cages -the so-called [6,6] bonds -participate effectively in numerous chemical reactions, of which cyclopropanations [12][13][14] and 1,3dipolar cycloadditions [15][16][17] are amongst the most commonly used. The electron-deficient nature of C 60 , C 70 , and higher fullerenes also makes [6,6] bonds excellent dienophiles in Diels-Alder (DA) cycloadditions. ...
... Further elution with toluene gave compound 3 a (34.1 mg, 56% yield) as a dark brown solid. 13 ...
... Et 3 SiH (0.15 mL, 0.9 mmol) and BF 3 ·Et 2 O (0.1 mL, 0.81 mmol) was then added and the resulting mixture was stirred for 5 h at room temperature (TLC monitoring) and directly subjected to column chromatography on silica using toluene as the eluent to provide compound 5 a (82.1 mg, 82%) as a dark brown solid. 13 25,161.40 (only the major product α-6 a is identified); UV-vis (toluene) λ max (nm): 398, 449 (only the major product α-6 a is identified); ESI-HRMS (m/z) calculated for [M + Na] + = 1140,1029; found 1140.0985. ...
Article
A synthetic methodology is reported that functionalizes C60 and C70 fullerenes with dihydroazepine rings by a cascade reaction encompassing a rhodium-catalyzed cycloisomerization of 1,5-bisallenes and a [4+2] cycloaddition. This transition-metal catalyzed cascade reaction provides a versatile and step-economical approach to the synthesis of 6,7-membered polyheterocyclic fullerene adducts. Electrochemical characterization of the products obtained ventures their application in organic and perovskite photovoltaic devices.
... In this regard, during the last years different studies have revealed important antiviral activity developed by [60]fullerene derivatives. In particular, by hexakis-adducts of [60]fullerene highly derivatized with biomolecules such as carbohydrates [6][7][8][9][10] and amino acids [11]. These hexakis-adducts present icosahedral geometry, are soluble in biological media, and are not cytotoxic. ...
... Furthermore, the CuAAC reaction can be difficulted by the copper chelating ability of carbohydrates, especially when highly multivalent derivatives are prepared. In order to increase the multivalency of the fullerene hexakis-adducts and tridecafullerenes, we developed a copper-free SPAAC strategy [18,19] which led to the preparation of molecular tridecafullerenes appended with 360 disaccharides [9]. In this case, the use of a SPAAC reaction was required owing to the ability of α(1,2)mannobiosides to chelate the copper between the two monosaccharide units. ...
... As outlined before, this methodology presents some advantages when compared with CuAAC. From a synthetic point of view, although both methodologies exhibit high yields, SPAAC usually takes shorter reaction times to be completed (30 min under MW) [9,19], in contrast to CuAAC which normally requires from 48 h to 72 h. This represents an important advantage when biological applications come into play. ...
Article
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The synthesis of new biocompatible antiviral materials to fight against the development of multidrug resistance is being widely explored. Due to their unique globular structure and excellent properties, [60]fullerene-based antivirals are very promising bioconjugates. In this work, fullerene derivatives with different topologies and number of glycofullerene units were synthesized by using a SPAAC copper free strategy. This procedure allowed the synthesis of compounds 1-3, containing from 20 to 40 mannose units, in a very efficient manner and in short reaction times under MW irradiation. The glycoderivatives were studied in an infection assay by a pseudotyped viral particle with Ebola virus GP1. The results obtained show that these glycofullerene oligomers are efficient inhibitors of EBOV infection with IC50s in the nanomolar range. In particular, compound 3, with four glycofullerene moieties, presents an outstanding relative inhibitory potency (RIP). We propose that this high RIP value stems from the appropriate topological features that efficiently interact with DC-SIGN.
... [23] With this background, inhibition of DC-SIGN-mediated attachment of viral particles to innate immune cells represents a promising strategy for the development of antiviral drugs. [24][25][26] In the past, this strategy has been investigated for the treatment of HIV, [20] ebola, [27] zika, [28] and dengue infections. [28] In view of the recent emergence of the SARS-CoV-2 pandemic, DC-SIGN-targeted antivirals could represent a promising host-directed treatment option for COVID-19. ...
... [24][25][26] In the past, this strategy has been investigated for the treatment of HIV, [20] ebola, [27] zika, [28] and dengue infections. [28] In view of the recent emergence of the SARS-CoV-2 pandemic, DC-SIGN-targeted antivirals could represent a promising host-directed treatment option for COVID-19. Importantly, metabolic pathways responsible for glycosylation of viral proteins, as well as the targeted glycan receptors are evolutionarily conserved in the host genome. ...
... This mechanism leads to an increase in apparent binding affinity of protein-carbohydrate interactions of up to a factor of 10 6 . [32,33] In this context, functionalized polymeric supports, [34] peptides, [35] dendrimers, [36] nanoparticles, [37] fullerenes, [28] carbon nanotubes, [27] and thiacalixarenes [38] have been studied. However, a severe drawback of some of these nonbiodegradable multivalent scaffolds is their potential accumulation and associated toxicity, especially when prolonged pulmonary applications are considered. ...
Preprint
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Envelope glycoproteins of many viruses are heavily glycosylated. Among other functions, virus glycans can mediate interactions with host receptors and contribute to internalization and virus dissemination. The C-type lectin receptor DC-SIGN, which is expressed by cells of the innate immune system, can act as an entry receptor for pathogens, including pandemic viruses such as SARS-CoV-2, ebola, and HIV. In the context of the recent SARS-CoV-2 pandemic, this mechanism has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral envelope glycoproteins has therefore the potential to generate broad spectrum antivirulent agents. Moreover, the important role of this mechanism in numerous viral infections, as well as an interaction partner conserved in the host genome highlight the potential of DC-SIGN-targeted therapeutics not only for the treatment of existing infections, but also for the rapid response to future pandemics with newly emerging virus serotypes. Here, we demonstrate that mannose-functionalized poly-L-lysine glycoconjugates efficiently inhibit the attachment of viral glycoproteins from SARS-CoV-2, ebola, and HIV to DC-SIGN-presenting cells with up to picomolar affinity. Treatment of susceptible cells leads to prolonged receptor internalization and statistically significant inhibition of virus binding for up to 6 h. Furthermore, the polymers are fully biocompatible and readily cleared by the target cells. Finally, the thermodynamic analysis of these multivalent interactions revealed an entropy-driven affinity enhancement, opening promising perspectives for the future development of multivalent therapeutics.
... 142 Recently, tridecafullerenes appended with up to 360 1,2mannobiose molecules showed outstanding antiviral activity against zika virus (ZIKV) and dengue virus (DENV). 24 Examples of antiviral studies performed with fullerenes and their derivatives are summarized in Table 1. ...
... To perform this count of studies, only CBNs with different chemical structural forms were considered. Thus, fullerene and its derivatives showed antiviral activity in nine studies against HIV-1, 26, 135, 137, 139− 141, 143, 144 five studies against HIV-2 26,139−141,143,144 out of six, and against other viruses such as SIV, 138 M-MuLV, 138 HCV, 142 ZIKV, 24 and DENV. 24 Carbon dots and their derivatives exhibited antiviral activity against HCoV, 22 HIV-1, 61 JEV, 146 ZIKV, 146 DENV, 146 PEDV 54 and two studies against PRRSV. ...
... Thus, fullerene and its derivatives showed antiviral activity in nine studies against HIV-1, 26, 135, 137, 139− 141, 143, 144 five studies against HIV-2 26,139−141,143,144 out of six, and against other viruses such as SIV, 138 M-MuLV, 138 HCV, 142 ZIKV, 24 and DENV. 24 Carbon dots and their derivatives exhibited antiviral activity against HCoV, 22 HIV-1, 61 JEV, 146 ZIKV, 146 DENV, 146 PEDV 54 and two studies against PRRSV. 54,63 Graphene and related CBNs have shown antiviral activity against HIV-1 in four studies out of five, 147,148,154 five studies against PEDV out of seven, 28,152 two studies against FCoV, 151,155 and one study against PRRSV 152 and SARS-CoV-2. ...
Article
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Therapeutic options for the highly pathogenic human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the current pandemic coronavirus disease (COVID-19) are urgently needed. COVID-19 is associated with viral pneumonia and acute respiratory distress syndrome causing significant morbidity and mortality. The proposed treatments for COVID-19 have shown little or no effect in the clinic so far. Additionally, bacterial and fungal pathogens contribute to the SARS-CoV-2-mediated pneumonia disease complex. The antibiotic resistance in pneumonia treatment is increasing at an alarming rate. Therefore, carbon-based nanomaterials (CBNs), such as fullerene, carbon dots, graphene, and their derivatives constitute a promising alternative due to their wide-spectrum antimicrobial activity, biocompatibility, biodegradability, and capacity to induce tissue regeneration. Furthermore, the antimicrobial mode of action is mainly physical (e.g., membrane distortion), characterized by a low risk of antimicrobial resistance. In this Review, we evaluated the literature on the antiviral activity and broad-spectrum antimicrobial properties of CBNs. CBNs had antiviral activity against 13 enveloped positive-sense single-stranded RNA viruses, including SARS-CoV-2. CBNs with low or no toxicity to humans are promising therapeutics against the COVID-19 pneumonia complex with other viruses, bacteria, and fungi, including those that are multidrug-resistant.
... [22] With this background, inhibition of DC-SIGN-mediated attachment of viral particles to innate immune cells represents a promising strategy for the development of antiviral drugs. [23][24][25] In the past, this strategy has been investigated for the treatment of HIV, [26] ebola, [27] zika, [28] and dengue infections. [28] In view of the recent emergence of the SARS-CoV-2 pandemic, DC-SIGN-targeted antivirals could represent a promising hostdirected treatment option for COVID-19. ...
... [23][24][25] In the past, this strategy has been investigated for the treatment of HIV, [26] ebola, [27] zika, [28] and dengue infections. [28] In view of the recent emergence of the SARS-CoV-2 pandemic, DC-SIGN-targeted antivirals could represent a promising hostdirected treatment option for COVID-19. Importantly, metabolic pathways responsible for glycosylation of viral proteins, as well as the targeted glycan receptors are evolutionarily conserved in the host genome. ...
... This mechanism leads to an increase in apparent binding affinity of protein-carbohydrate interactions of up to a factor of 10 6 . [32,33] In this context, functionalized polymeric supports, [34] peptides, [35] dendrimers, [36] nanoparticles, [37] fullerenes, [28] carbon nanotubes, [27] and thiacalixarenes [38] have been studied. However, a severe drawback of some of these non-biodegradable multivalent scaffolds is their potential accumulation and associated toxicity, especially when prolonged pulmonary applications are considered. ...
Article
The C‐type lectin receptor DC‐SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS‐CoV‐2, ebola, and HIV and contributes to virus internalization and dissemination. In the context of the recent SARS‐CoV‐2 pandemic, involvement of DC‐SIGN has been linked to severe cases of COVID‐19. Inhibition of the interaction between DC‐SIGN and viral glycoproteins has the potential to generate broad spectrum antiviral agents. Here, we demonstrate that mannose‐functionalized poly‐ l ‐lysine glycoconjugates efficiently inhibit the attachment of viral glycoproteins to DC‐SIGN‐presenting cells with picomolar affinity. Treatment of these cells leads to prolonged receptor internalization and inhibition of virus binding for up to 6 h. Furthermore, the polymers are fully bio‐compatible and readily cleared by target cells. The thermodynamic analysis of the multivalent interactions reveals enhanced entropy‐driven affinities and promising perspectives for the future development of multivalent therapeutics.
... Moreover, the mechanism of action depends on the interaction with the host cells, and while injected at the different time intervals, it prevents the virus from damaging the host cells. The well-developed surface chemistry of the glycofullerenes was very effective in the current pandemic virus SARS-CoV-2 which involves the click chemistry strategy to anchor the ligands by inhibiting the virus [98,99]. ...
Article
Novel coronavirus disease 2019 (COVID-19) is by far the worst pandemic disease in the current millennium. The first human-to-human transmission was observed in December 2019 in China and is caused by the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has infected millions of people within months across the globe. SARS-CoV-2 is a spike protein enveloped virus with particle-like characteristics and a diameter of 60–140 nm. Real-time PCR, reverse transcriptase PCR, isothermal PCR, immunological-based detection technique and nano-based diagnostic system have been explained for the identification and differentiation of different types of virus including SARS-COV-2. Synthetic nanoparticles can closely mimic the virus and interact strongly with its virulent proteins due to their morphological similarities. Some of the antiviral nanomaterials are also discussed, for example zinc oxide nanoparticle is an antiviral agent with a tetrapod morphology that mimics the cell surface by interacting with the viral capsid. It suppressed the viral proteins upon UV radiation due to reaction caused by photocatalysis. Hence, nanoparticle-based strategies for tackling viruses have immense potential. The second part of the review points to the latest in vitro and in vivo procedures for screening viral particles and the usage of nanoparticles in diagnostic and therapeutics. This would be beneficial for early detection and assists for the safe and effective therapeutic management of COVID-19.
... [12b] Recently, tridecafullerenes bearing up to 360 disaccharides efficiently inhibited infection by emergent viruses, namely Zika and Dengue, at picomolar concentrations. [16] On the other hand, molecules containing amino acids covalently attached to the C 60 fullerene core have been known since 1993, [17] and different fullerene amino acids have been used as synthons to create larger structures in which the carbon sphere was inserted into a peptide backbone. [4c,18] These amino acid-or peptide-decorated fullerene derivatives also display antiviral, antimicrobial, or antioxidant activities, or can be used as drug delivery systems. ...
Article
Full-text available
Unprecedented 3D hexa‐adducts of [60]fullerene peripherally decorated with twelve tryptophan (Trp) or tyrosine (Tyr) residues have been synthesized. Studies on the antiviral activity of these novel compounds against HIV and EV71 reveal that they are much more potent against HIV and equally active against EV71 than the previously described dendrimer prototypes AL‐385 and AL‐463 , which possess the same number of Trp/Tyr residues on the periphery but attached to a smaller and more flexible pentaerythritol core. These results demonstrate the relevance of the globular 3D presentation of the peripheral groups (Trp/Tyr) as well as the length of the spacer connecting them to the central core to interact with the viral envelopes, particularly in the case of HIV, and support the hypothesis that [60]fullerene can be an alternative and attractive biocompatible carbon‐based scaffold for this type of highly symmetrical dendrimers. In addition, the functionalized fullerenes here described, which display twelve peripheral negatively charged indole moieties on their globular surface, define a new and versatile class of compounds with a promising potential in biomedical applications.
... In this context, in a joint effort with other research groups, we have reported the synthesis of several multivalent mannose-decorated glycoconjugates able to efficiently target and block the cellular receptor DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) [15]. Among all the conjugates prepared, the syntheses of giant glycofullerenes [16][17][18] and nanocarbon-based glycoconjugates [19] with antiviral activity have been recently reported. Despite those encouraging results, these artificial systems still face some limitations such as a relatively complex and expensive synthesis, which hampers their preparation in a multigram scale for clinical uses. ...
Article
Carbohydrate multivalent interactions play a key role in nature as efficient recognition tools for controlling a plethora of physiological and pathological events. These interactions are weak but the presence of multiple copies of ligands and receptors on biological surfaces leads to a multivalent recognition with enhanced selectivity and exponentially increased affinity. Here we report a simple and straightforward methodology for multivalent presentation of both simple monosaccharide ligands and complex dendritic glycostructures using polymeric nanogels (NGs). The interaction between the glycoNGs and a model lectin has been analysed by DLS and UV–Vis agglutination assays, showing that the introduction of glycodendrons with 3 and 9 mannose residues into the NGs results in a strong enhancement of the multivalency.
... Dendrimers and dendronized materials, such as fullerenes and carbon nanotubes, have also promising activity against other viruses like SARS-CoV-2 [78], Figure 5A; Ebola virus [88], Figure 5B; Zika and Dengue viruses [89], Figure 5C; HSV [90]; cytomegalovirus [91]; some flavivirus, such as the responsible of the Japanese encephalitis [92]; and different human or aviary flu viruses [93]. ...
Article
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Infectious diseases are one of the main global public health risks, predominantly caused by viruses, bacteria, fungi, and parasites. The control of infections is founded on three main pillars: prevention, treatment, and diagnosis. However, the appearance of microbial resistance has challenged traditional strategies and demands new approaches. Dendrimers are a type of polymeric nanoparticles whose nanometric size, multivalency, biocompatibility, and structural perfection offer boundless possibilities in multiple biomedical applications. This review provides the reader a general overview about the uses of dendrimers and dendritic materials in the treatment, prevention, and diagnosis of highly prevalent infectious diseases, and their advantages compared to traditional approaches. Examples of dendrimers as antimicrobial agents per se, as nanocarriers of antimicrobial drugs, as well as their uses in gene transfection, in vaccines or as contrast agents in imaging assays are presented. Despite the need to address some challenges in order to be used in the clinic, dendritic materials appear as an innovative tool with a brilliant future ahead in the clinical management of infectious diseases and many other health issues.
... Falynskova et al. [16] produced a tailor-made fullerene compound fullerene-(tris-aminocaproic acid) hydrate to hinder the Respiratory Syncytial Virus multiplication in HEp-2 cell, however application time is crucial for effective inhibition of the virus. Fullerene derivatives are also able to inhibit the Zika Virus and Dengue viruses [17] . Non-derivatized fullerene is also employed for efficient inhibition of viruses like simian immunodeficiency virus and the Moloney murine leukemia virus (M-MuLV) [18] . ...
Article
Full-text available
The rapid outbreaks of lethal viruses necessitate the development of novel antiviral substance. Besides the conventional antiviral substances, biocompatible nanomaterials also have significant potential in combating the virus at various stages of infection. Carbon nanomaterials have an impressive record against viruses and can deal with many crucial healthcare issues. In accordance with the published literature, biocompatible carbon nanomaterials have a promising prospect as an antiviral substance. Subsequently, the antiviral properties of different carbon nanomaterials namely fullerene, carbon nanotube, carbon dot and graphene oxide have been reviewed.
... The viral infection cycle begins with binding to the receptors on the host cell membrane. Therefore, inhibiting viral entry via a binding decoy has been proved to be effective for many types of viruses, e.g., the use of multivalent mannose structures is reported to be effective for inhibiting Ebola virus infection, which is one of few options to fight Ebola infection (9)(10)(11)(12). For IAV, two glycoproteins have been identified to be associated with the binding behavior on the cellular membrane, hemagglutinin (HA) and neuraminidase (NA). ...
Article
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Here, we report the topology-matched design of heteromultivalent nanostructures as potent and broad-spectrum virus entry inhibitors based on the host cell membrane. Initially, we investigate the virus binding dynamics to validate the better binding performance of the heteromultivalent moieties as compared to homomultivalent ones. The heteromultivalent binding moieties are transferred to nanostructures with a bowl-like shape matching the viral spherical surface. Unlike the conventional homomultivalent inhibitors, the heteromultivalent ones exhibit a half maximal inhibitory concentration of 32.4 ± 13.7 μg/ml due to the synergistic multivalent effects and the topology-matched shape. At a dose without causing cellular toxicity, >99.99% reduction of virus propagation has been achieved. Since multiple binding sites have also been identified on the S protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), we envision that the use of heteromultivalent nanostructures may also be applied to develop a potent inhibitor to prevent coronavirus infection.
... In recent years, a series of innovative nanomaterials with potential activities against various viruses have been reported to play an important role in preventing and treating different viral infections [4][5][6][7][8], such as DNA origami [9], graphene nanosheets [10,11], fullerene nanospheres [12][13][14], macromolecular polymers [15], nano hydrogels [16][17][18], and other emerging materials [19,20]. These nanomaterials can play an antiviral role in the different stages of the virus life cycle, but their further application was restricted by the low synthesis yield and the complex synthesis procedures, suggesting the rare advantage of the one-pot method for rapid and large-scale synthesis of antiviral nanomaterials with good reproducibility. ...
Article
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Background The infection and spread of porcine reproductive and respiratory syndrome virus (PRRSV) pose a serious threat to the global pig industry, and inhibiting the viral infection process is a promising treatment strategy. Nanomaterials can interact with viruses and have attracted much attention due to their large specific surface area and unique physicochemical properties. Ferrous sulfide nanoparticles (FeS NPs) with the characteristics of high reactivity, large specific surface area, and low cost are widely applied to environmental remediation, catalysis, energy storage and medicine. However, there is no report on the application of FeS NPs in the antiviral field. In this study, gelatin stabilized FeS nanoparticles (Gel-FeS NPs) were large-scale synthesized rapidly by the one-pot method of co-precipitation of Fe ²⁺ and S 2‒ . Results The prepared Gel-FeS NPs exhibited good stability and dispersibility with an average diameter of 47.3 nm. Additionally, they were characterized with good biocompatibility and high antiviral activity against PRRSV proliferation in the stages of adsorption, invasion, and replication. Conclusions We reported for the first time the virucidal and antiviral activity of Gel-FeS NPs. The synthesized Gel-FeS NPs exhibited good dispersibility and biocompatibility as well as effective inhibition on PRRSV proliferation. Moreover, the Fe ²⁺ released from degraded Gel-FeS NPs still displayed an antiviral effect, demonstrating the advantage of Gel-FeS NPs as an antiviral nanomaterial compared to other nanomaterials. This work highlighted the antiviral effect of Gel-FeS NPs and provided a new strategy for ferrous-based nanoparticles against PRRSV. Graphical Abstract
... In this case, the molecule was synthesized with a C 60 tridecafullerene bearing α(1,2)mannobioside. 70 The use of this disaccharide was already investigated, showing an increase of affinity with DC-sign receptors by a factor of 3−4. 71 The synthetic strategy exploited also the use of strainpromoted copper-free cycloaddition of azides to alkynes (SPAAC) for the coupling of the core fullerene to the surrounding fullerenes. ...
... Small fragments of the Man 9 epitope have been synthesised and evaluated in different glycomimetic systems in pursuit of sugars simpler than Man 9 but with reasonable binding affinities for DC-SIGN. [12][13][14][15] Recently, we have developed a straightforward synthetic strategy for the preparation of the Man 9 epitope with the natural beta configuration at the reducing end. 16 Although the synthesis that we have described is competitive with those published previously by other laboratories, the preparation of the β-mannose unit remains the limiting step. ...
Article
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High-mannose (Man9GlcNAc2) is the main carbohydrate unit present in viral envelope glycoproteins such as gp120 of HIV and the GP1 of Ebola virus. This oligosaccharide comprises the Man9 epitope conjugated to two terminal N-acetylglucosamines by otherwise rarely-encountered β-mannose glycosidic bond. Formation of this challenging linkage is the bottleneck of the few synthetic approaches described to prepare high mannose. Herein, we report the synthesis of the Man9 epitope with both alpha and beta configurations at the reducing end, and subsequent evaluation of the impact of this configuration on binding to natural receptor of high-mannose, DC-SIGN. Using fluorescence polarization assays, we demonstrate that both anomers bind to DC-SIGN with comparable affinity. These relevant results therefore indicate that the more synthetically-accesible Man9 alpha epitope may be deployed as ligand for DC-SIGN in both in vitro and in vivo biological assays.
... Such mechanism of action was recently demonstrated for nanoballs of tridecafullerenes appended with up to 360 1,2-mannobioside units. These particles inhibited entry of ZIKV and Dengue viruses (DENV) to the host cell by blocking the intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) [27,28]. While they are effective as antivirals, the synthesis is demanding. ...
Article
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A series of anionic homopolymers, poly(sodium 2-(acrylamido)-2-methyl-1-propanesulfonate) (PAMPS) and amphiphilic copolymers of AMPS and sodium 11-(acrylamido)undecanoate (AaU), both block (PAMPS75-b-PAaUn), and random (P(AMPSm-co-AaUn)), were synthesized and their antiviral activity against Zika virus (ZIKV) was evaluated. Interestingly, while the homopolymers showed limited antiviral activity, the copolymers are very efficient antivirals. This observation was explained considering that under the conditions relevant to the biological experiments (pH 7.4 PBS buffer) the macromolecules of these copolymers exist as negatively charged (zeta potential about −25 mV) nanoparticles (4–12 nm) due to their self-organization. They inhibit the ZIKV replication cycle by binding to the cell surface and thereby blocking virus attachment to host cells. Considering good solubility in aqueous media, low toxicity, and high selectivity index (SI) of the PAMPS-b-PAaU copolymers, they can be considered promising agents against ZIKV infections.
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Starting from an enantiopure 3-azido-substituted pyran derivative and various oligo-alkynes a series of multivalent 1,2,3-triazole-linked carbohydrate mimetics was synthesized. The copper-catalyzed Huisgen–Meldal-Sharpless cycloaddition (CuAAC) served as key coupling reaction. Cu/C in the presence of triethylamine proved to be a good catalytic system in most cases. Tri-, tetra-, hexa-, and octavalent compounds with typical rigid or flexible core units were prepared. The most complex compound contains a C60-fullerene center leading to a dodecavalent carbohydrate mimetic. Only a few of the multivalent target compounds could be converted into pure O-sulfated derivatives that are required for their evaluation as L- and P-selectin ligands. Nevertheless, preliminary experiments suggest that the dodecavalent C60-derived compound may be a promising ligand of these biologically important proteins with IC50 values in the low nanomolar range. © 2020 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH
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A new, general and practical method for the preparation of novel and diverse [60]fullerene-fused spiro[4,5]/[5,5] derivatives through palladium-catalyzed domino spirocyclization was developed.
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Here we report the Friedel–Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with thiophene-based methyl esters. While C60Cl6 formed expected Cs-C60R5Cl products, C70Cl8 demonstrated a tendency for both substitution of chlorine atoms and addition of an extra thiophene unit, thus forming Cs-C70R8 and C1-C70R9H compounds. The synthesized water-soluble C60 and C70 fullerene derivatives with thiophene-based addends demonstrated high activity against a broad range of viruses, including human immunodeficiency virus, influenza virus, cytomegalovirus, and herpes simplex virus. The record activity of C70 fullerene derivatives against herpes simplex virus together with low toxicity in mice makes them promising candidates for the development of novel non-nucleoside antiherpetic drugs.
Article
Antivirals are now more important than ever. To efficiently inhibit virus replication, antiviral multivalent strategies need sufficient affinity to overcome the excellent matching between the virus and its receptor. This report highlights a phage capsid scaffold strategy that can be used to precisely position sialic acid moieties to inhibit influenza A virus replication. Cell‐virus interactions, which are usually mediated by the recognition of carbohydrates, can be disrupted to prevent viral infection. However, to act as efficient inhibitors, the competitor molecules not only have to present multiple copies of the ligand, but also match the binding sites of the virus receptor. Here, the use of sialylated phage capsid nanoparticles to inhibit influenza virus infection is highlighted.
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Novel [60]fullerene‐steroid hybrids have been synthesized by Bingel−Hirsch cyclopropanation reaction between C60 and steroid malonates, leading to conjugates in which a [60]fullerene unit is connected to one or two dehydroepiandrosterone moieties, an important naturally occurring steroid hormone. The obtained derivatives have been fully characterized by a whole set of instrumental techniques in order to determine their chemical structure. Moreover, their electrochemical properties, investigated by cyclic voltammetry, revealed the presence of three reversible reduction waves for both hybrids. Furthermore, Transmission Electron Microscopy studies allowed to determine the morphology and size of the fullerene hybrids in aqueous solution, showing a tendency to organize into spherical nanoscale structures. Theoretical calculations using the DFT‐PBE method and 6‐311G(d,p) basis set, were performed to predict the most stable conformations for the synthesized compounds, and to determine the factors that control the geometry of these hybrid molecules. In addition, parameters such as polarity, and lipophilicity were estimated. The obtained results corroborate the predicted activity against HIV‐1 protease as suggested by molecular docking simulation.
Article
The rise in human pandemics demands prudent approaches in antiviral material development for disease prevention and treatment via effective protective equipment and therapeutic strategy. However, the current state of the antiviral materials research is predominantly aligned towards drug development and its related areas, catering to the field of pharmaceutical technology. This review distinguishes the research advances in terms of innovative materials exhibiting antiviral activities that take advantage of fast‐developing nanotechnology and biopolymer technology. Essential concepts of antiviral principles and underlying mechanisms are illustrated, followed with detailed descriptions of novel antiviral materials including inorganic nanomaterials, organic nanomaterials and biopolymers. The biomedical applications of the antiviral materials are also elaborated based on the specific categorization. Challenges and future prospects are discussed to facilitate the research and development of protective solutions and curative treatments.
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A family of hexakis-substituted [60]fullerene adducts endowed with the well-known tridentate 2,6-bis(pyrazol-1-yl)pyridine (bpp) ligand for spin-crossover (SCO) systems has been designed and synthesized. It has been experimentally and theoretically demonstrated that these molecular scaffolds are able to form polynuclear SCO complexes in solution. UV-vis and fluorescence spectroscopy studies have allowed monitoring of the formation of up to six Fe(II)–bpp SCO complexes. In addition, DFT calculations have been performed to model the different complexation environments and simulate their electronic properties. The complexes retain SCO properties in the solid state exhibiting both thermal- and photoinduced spin transitions, as confirmed by temperature-dependent magnetic susceptibility and Raman spectroscopy measurements. The synthesis of these complexes demonstrates that [60]fullerene hexakis-adducts are excellent and versatile platforms to develop polynuclear SCO systems in which a fullerene core is surrounded by a SCO molecular shell.
Article
Highly efficient reactions that enable the assembly of molecules into complex structures have driven extensive progress in synthetic chemistry. In particular, reactions that occur under mild conditions and in benign solvents, produce no by-products, and rapidly reach completion are attracting significant attention. Amongst these, the strain-promoted azide-alkyne cycloaddition, involving various cyclooctyne derivatives reacting with azide-bearing molecules, has gained extensive popularity in organic synthesis and bioorthogonal chemistry. This reaction has also recently gained momentum in polymer chemistry, where it has been used to decorate, link, crosslink, and even prepare polymer chains. This survey highlights key recent achievements in the use of this reaction to produce a variety of polymeric constructs for disparate applications.
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Multi‐functionalization and isomer‐purity of fullerenes are crucial tasks for the development of fullerene chemistry in various fields. In both current main approaches – tether‐directed covalent functionalization and supramolecular masks – the control of regioselectivity requires multi‐step synthetic procedures to prepare the desired tether or mask. Herein, we describe light‐responsive tethers, containing an azobenzene photoswitch and two malonate groups, in the double cyclopropanation of [60]fullerene. The formation of the bis‐adducts and their spectroscopic and photochemical properties, as well as the effect of azobenzene photoswitching on the regiochemistry of the bis‐addition, have been studied. The behavior of the tethers depends on the geometry of the connection between the photoactive core and the malonate moieties. One tether lead to strikingly different adduct distribution for the E and Z isomers, indicating that the covalent bis‐functionalization of C60 can be controlled by light.
Article
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By incorporating azobenzene photochromic units in the double functionalization of [60]fullerene, the regiochemistry of the double cyclopropanation reaction could be controlled by using either the E or the Z isomeric forms of the photoswitch. Once covalently linked to the C60 sphere, the azobenzene unit changes its light‐ and thermally‐induced isomerization properties. Abstract Multi‐functionalization and isomer‐purity of fullerenes are crucial tasks for the development of their chemistry in various fields. In both current main approaches—tether‐directed covalent functionalization and supramolecular masks—the control of regioselectivity requires multi‐step synthetic procedures to prepare the desired tether or mask. Herein, we describe light‐responsive tethers, containing an azobenzene photoswitch and two malonate groups, in the double cyclopropanation of [60]fullerene. The formation of the bis‐adducts and their spectroscopic and photochemical properties, as well as the effect of azobenzene photoswitching on the regiochemistry of the bis‐addition, have been studied. The behavior of the tethers depends on the geometry of the connection between the photoactive core and the malonate moieties. One tether lead to a strikingly different adduct distribution for the E and Z isomers, indicating that the covalent bis‐functionalization of C60 can be controlled by light.
Article
An unprecedented multicomponent domino reaction of [60]fullerene, indole, and DMSO/HCl has been developed for the one-pot efficient synthesis of diverse N-substituted [60]fulleroindole derivatives. This methodology features simple operation, low cost, and transition-metal-circumvented and good functional group tolerance in indole.
Article
Glycodendrimers are an important class of synthetic macromolecules that can be used to mimic many structural and functional features of cell surface glycoconjugates. Their carbohydrate moieties perform key important functions in bacterial and viral infections, often regulated by carbohydrate-protein interactions. Several studies have shown that the molecular structure, the valency and spatial organization of carbohydrate epitopes in glycoconjugates are key factors in the specificity and avidity of carbohydrate-protein interactions. Choosing the right glycodendrimers almost always helps to interfere in such interactions and blocks bacteria o viral adhesion or entry into host cells as an effective strategy to inhibit bacterial or viral infections. In this review, we describe the state of the art in the design and synthesis of glycodendrimers employed for the development of anti-adhesion therapy against bacterial and viral infections.Glycodendrimers are an important class of synthetic macromolecules that can be used to mimic many structural and functional features of cell surface glycoconjugates. Their carbohydrate moieties perform key important functions in bacterial and viral infections, often regulated by carbohydrate-protein interactions. Several studies have shown that the molecular structure, the valency and spatial organization of carbohydrate epitopes in glycoconjugates are key factors in the specificity and avidity of carbohydrate-protein interactions. Choosing the right glycodendrimers almost always helps to interfere in such interactions and blocks bacteria o viral adhesion or entry into host cells as an effective strategy to inhibit bacterial or viral infections. In this review, we describe the state of the art in the design and synthesis of glycodendrimers employed for the development of anti-adhesion therapy against bacterial and viral infections.
Preprint
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The rapid outbreaks of lethal viruses necessitate the development of novel antiviral substance. Besides the conventional antiviral substances, biocompatible nanomaterials also have significant potential in combating the virus at various stages of infection. Carbon nanomaterials have an impressive record against viruses and can deal with many crucial healthcare issues. In accordance with the published literature, biocompatible carbon nanomaterials have a promising prospect as an antiviral substance. Subsequently, the antiviral properties of different carbon nanomaterials namely fullerene, carbon nanotube, carbon dot and graphene oxide have been reviewed.
Article
We have serendipitously discovered a reaction of phthalaldehyde with tosylhydrazide and alcohols, used as solvents, resulting in the formation of the corresponding phthalazinium salts. The obtained salts represent convenient precursors for the generation of azomethine ylides and readily functionalize the fullerene C60 upon treatment with a base to produce a new family of fullerene derivatives bearing pyrrolidino[2,1–a]phthalazine moiety on the fullerene cage. The revealed reaction provides a convenient synthetic route for the preparation of a broad variety of fullerene derivatives incorporating the substituents stemming from readily accessible alcohols. The obtained fullerene derivatives were investigated as electron transport materials in p-i-n perovskite solar cells and delivered encouraging power conversion efficiencies of >14%. The ease of the preparation and tunability of optoelectronic properties of pyrrolidino[2,1–a]phthalazino[60]fullerenes makes them highly promising materials for organic electronics and photovoltaics. This article is protected by copyright. All rights reserved.
Article
Japanese encephalitis is a mosquito-borne disease caused by the Japanese encephalitis virus (JEV) that is prevalent in Asia and the Western Pacific. Currently, there is no effective treatment for Japanese encephalitis. Curcumin is a compound extracted from the roots of Curcuma longa, and many studies have reported its antiviral and anti-inflammatory activities. However, the high cytotoxicity and very low solubility of curcumin limit its biomedical applications. In this study, curcumin carbon quantum dots (Cur-CQDs) were synthesized by mild pyrolysis-induced polymerization and carbonization, leading to higher water solubility and lower cytotoxicity, as well as superior antiviral activity against JEV infection. We found that Cur-CQDs effectively bound to the E protein of JEV, preventing viral entry into the host cells. In addition, after continued treatment of JEV with Cur-CQDs, a mutant strain of JEV was evolved that did not support binding of Cur-CQDs to the JEV envelope. Using transmission electron microscopy, bio-layer interferometry, and molecular docking analysis, we revealed that the S123R and K312R mutations in the E protein play a key role in binding Cur-CQDs. The S123 and K312 residues are located in structural domains II and III of the E protein, respectively, and are responsible for binding to receptors on and fusing with the cell membrane. Taken together, our results suggest that the E protein of flaviviruses represents a potential target for the development of CQD-based inhibitors to prevent or treat viral infections.
Thesis
The work presented in this thesis focused on the preparation and characterization of novel stimuli-responsive organosilica particles. In this respect, a series of organoalkoxysilanes have been synthesized and used to prepare organosilicas, which possess either covalently or supramolecularly linked organic bridging-groups within their silica framework. It has been shown that porous and light-degradable and organosilicas can be prepared which are able to quantitatively release hydrophobic molecules upon light-irradiation and that oligonucleotides, such as DNA and PNA can be integrated into the particles framework in order to prepare materials, which can interact with biological molecules such as enzyme or complementary DNAs. Finally, the possibility to prepare redox-responsive cage-like organosilica particles, a novel type of morphology for organosilicas, was shown and their potential use for the development of novel nanomedicines was evaluated and discusse.
Article
Fullerenes have attracted considerable attention for their possible use in human therapy. Pure C60 is soluble only in some organic solvents, but this could be overcome by chemical modifications. This review investigates the derivatization strategies and biological applications of fullerene C60 by using polar “active” molecules as sugars and amino acids/peptides that allow the increase of solubility in water. The effect of glycosylation on biological activity of fullerene can be divided in indirect and direct action. The “indirect action” of sugars correlates with their ability to make fullerene soluble in water but glycosylation can be also exploited for the target delivery; accordingly, glyco-derivatives of fullerenes have been investigated in PDT (photodynamic therapy), as inhibitors of in HIV-1 protease inhibition or against neurodegenerative diseases. The “direct action” involves fullerenes conjugated with sugars having a defined therapeutic role and the “multivalency” is the properties that ensure a good biological activity of glycofullerene derivatives. Increasing the sugars attached to fullerene intensifies the multivalency needed to efficiently use these glycosylated nanoparticles as potential ligands for receptors and enzymes that mediate the infection of viruses and bacteria (e.g. E. Coli, Ebola or Dengue viruses) for the infection. Also, amino acids-derivatives of fullerenes have been studied as anti-infective agents (against viruses such as cytomegalovirus and HIV), thanks to their immunological properties; derivatives as fullerenol or by linking tuftsin on a C60 core could be exploited as immunogenic nano-carriers. Alternatively fullerene conjugated with amino acids or peptides is investigated in the treatments of pathologies that request new approaches (Alzheimer, cancer, mixed connective tissue disease, lupus).
Article
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Bingel cyclopropanation between Buckminster fullerene and a heteroarmed malonate was utilized to produce a hexakis-functionalized C 60 core, with azide and tetrazine units. This orthogonally bifunctional C 60 scaffold can be selectively one-pot functionalized by two pericyclic click reactions, that is, inverse electron-demand Diels−Alder and azide−alkyne cycloaddition, which with appropriate ligands (monosaccharides, a peptide and oligonucleotides tested) allows one to control the assembly of heteroantennary bioconjugates.
Article
Nanomedicine is an emerging area that largely influences the efficacy of various therapies through the rational design of new materials exhibiting more targeted behavior. The synthetic effort, the amount of used material, and the cost are critical parameters to bear in mind if the production of the designed material is intended to be scaled for their widespread use. Even though materials science offers diverse options for different types of therapies, it is a difficult task to meet all the parameters mentioned above. The dendronization appears as an insightful approach to incorporate all the known benefits of the dendritic architecture by the attachment of dendrons to therapeutic agents, but in a much more affordable manner in terms of synthetic effort, amount of material, and cost. As will be presented, the most common dendrons used for biomedical applications are polyamide, polyester, carbosilane, polyether, and glycol-type, which are bonded to biological active molecules (BAMs), or molecular nanoplatforms (MPs) by hydrolysable bonds. Also relevant is the fact that the incorporation of dendrons not larger than third generation (G3) is sufficient to improve essential properties of these molecular systems, such as aqueous solubility, stability, and cellular internalization, among others. The type of dendron and its location on the BAMs or MPs, similar to placing a Lego piece on a model, will be decisive for obtaining the desired properties.
Article
As a result of increasing resistance among pathogens against antibiotics and anti-viral therapeutics, nanomaterials are attracting current interest as antimicrobial agents. Such materials offer triggered functionalities to combat challenging infections, based on either direct membrane action, effects of released ions, thermal shock induced by either light or magnetic fields, or oxidative photocatalysis. In the present overview, we focus on photocatalytic antimicrobial effects, in which light exposure triggers generation of reactive oxygen species. These, in turn, cause oxidative damage to key components in bacteria and viruses, including lipid membranes, lipopolysaccharides, proteins, and DNA/RNA. While an increasing body of studies demonstrate that potent antimicrobial effects can be achieved by photocatalytic nanomaterials, understanding of the mechanistic foundation underlying such effects is still in its infancy. Addressing this, we here provide an overview of the current understanding of the interaction of photocatalytic nanomaterials with pathogen membranes and membrane components, and how this translates into antibacterial and antiviral effects.
Article
Liquid-crystalline dendrimers with donor triphenylene as the peripheral discotic mesogens and acceptor fullerene as the dendrimer core have been designed and synthesized with the aim of achieving heterojunction ambipolar charge...
Article
An "umpolung relay" strategy, which includes an one-pot, twice polarity inversion cascade of C60 via carbanion and carbocation polarity reversed relay pathway, has been developed for the synthesis of a diverse range of novel [60]fulleroindole derivatives.
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An unprecedented ultra-long-lived triplet excited state (93 ms in water at 25 °C) has been measured for a globular glycodendrimeric tridecafullerene. The photophysics of S1 and T1, T1 quenching by O2 and N3⁻, and molecular modelling provide unequivocal evidence of the role played by the molecular design of the spacers connecting the core–shell C60 units and the C60-sugars on the degree of water solvation and its effect on this remarkable finding. Abstract Suitably engineered molecular systems exhibiting triplet excited states with very long lifetimes are important for high-end applications in nonlinear optics, photocatalysis, or biomedicine. We report the finding of an ultra-long-lived triplet state with a mean lifetime of 93 ms in an aqueous phase at room temperature, measured for a globular tridecafullerene with a highly compact glycodendrimeric structure. A series of three tridecafullerenes bearing different glycodendrons and spacers to the C60 units have been synthesized and characterized. UV/Vis spectra and DLS experiments confirm their aggregation in water. Steady-state and time-resolved fluorescence experiments suggest a different degree of inner solvation of the multifullerenes depending on their molecular design. Efficient quenching of the triplet states by O2 but not by waterborne azide anions has been observed. Molecular modelling reveals dissimilar access of the aqueous phase to the internal structure of the tridecafullerenes, differently shielded by the glycodendrimeric shell.
Article
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Suitably engineered molecular systems exhibiting triplet excited states with very long lifetimes are important for high‐end applications in nonlinear optics, photocatalysis or biomedicine. We report the finding of an ultra long‐lived triplet with a mean lifetime of 93 ms in aqueous phase at room temperature, measured for a globular tridecafullerene with a highly compact glycodendrimeric structure. A series of three tridecafullerenes bearing different glycodendrons and spacers to the C 60 units have been synthesized and characterized. UV/Vis spectra and DLS experiments prove their aggregation in water. Steady state and time‐resolved fluorescence experiments suggest a different degree of inner solvation of the multifullerenes depending on their molecular design. Efficient quenching of the triplet states by O 2 but not by waterborne azide anion has been observed. Molecular modelling reveals dissimilar access of the aqueous phase to the internal structure of the tridecafullerenes, differently shielded by the glycodendrimeric shell.
Article
DC-SIGN, a lectin discovered two decades ago, plays a relevant role in innate immunity. Since its discovery, it has turned to be a target to develop antiviral drugs based on...
Article
The reactions of C60 with acetone were carried out under basic condition in the presence of 1.0 M TBAOH (tetra-n-butylammonium hydroxide) methanol solution and ArCH2Br (Ar = Ph or o-BrPh), where methano[60]fulleroids with a novel 1,1,4,9,9,25-configuration were obtained and structurally characterized by single crystal diffraction. The product was formed via the ring-opening reaction of the [5,6]-cyclopropane by the nucleophilic addition of MeO-, which is different from the reactions of other ketones reported previously.
Article
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Fullerenes have unique structural and electronic properties that make them attractive candidates for diagnostic, therapeutic, and theranostic applications. However, their poor water solubility remains a limiting factor in realizing their full biomedical potential. Here, we present an approach based on a combination of supramolecular and covalent chemistry to access well-defined fullerene-containing polymer nanoparticles with a core-shell structure. In this approach, solvophobic forces and aromatic interactions first come into play to afford a micellar structure with a poly(ethylene glycol) shell and a corannulene-based fullerene-rich core. Covalent stabilization of the supramolecular assembly then affords core-crosslinked polymer nanoparticles. The shell makes these nanoparticles biocompatible and allows them to be dried to a solid and redispersed in water without inducing interparticle aggregation. The core allows a high content of different fullerene types to be encapsulated. Finally, covalent stabilization endows nanostructures with stability against changing environmental conditions.
Article
The first example of metal-free-catalyzed multicomponent annulation reaction of [60]fullerene has been developed for concise and efficient construction of novel [60]fullerene-fused 1,2-tetrahydrocarbazoles. Using inexpensive and readily available I2 as a catalyst, [60]fullerene, ketones, and indoles undergo a formal [2+2+2] annulation process to conveniently assemble diverse 1,2-tetrahydrocarbazoles. Mechanistic studies indicate that this reaction proceeds through I2-promoted generation of a 3-vinylindole structure with the characteristics of a conjugated diene followed by cycloaddition to [60]fullerene.
Article
A novel N-heterocyclic carbene-catalyzed three-component umpolung hydroalkylation of [60]fullerene with 4-(chloromethyl)-benzaldehydes/α,β-unsaturated aldehydes and alcohols/thioalcohols has been developed for the flexible and efficient preparation of diverse monoalkylated hydrofullerenes. Organic catalysis, broad substrate scope, excellent functional group tolerance, and products with high diversity and complexity levels are attractive features of this protocol.
Article
Carbohydrate-based materials offer exciting opportunities for drug delivery. They present readily available, biocompatible components for the construction of macromolecular systems which can be loaded with cargo, and can enable targeting of a payload to particular cell types through carbohydrate recognition events established in biological systems. These systems can additionally be engineered to respond to environmental stimuli, enabling triggered release of payload, to encompass multiple modes of therapeutic action, or to simultaneously fulfil a secondary function such as enabling imaging of target tissue. Here, we will explore the use of glycomacromolecules to deliver therapeutic benefits to address key health challenges, and suggest future directions for development of next-generation systems.
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Nowadays determining the disassembly mechanism of amyloids under nanomaterials action is a crucial issue for their successful future use in therapy of neurodegenerative and overall amyloid-related diseases. In this study the anti-amyloid disassembly activity of fullerenes C60 and C70 dispersed in 1-methyl-2-pyrrolidinone (NMP) towards amyloid fibrils preformed from lysozyme and insulin has been investigated using combination of different experimental techniques. Thioflavin T fluorescence assay and atomic force microscopy were applied for monitoring of disaggregation activity of fullerenes. It was demonstrated that both types of fullerene-based complexes are very effective in disassembling pre-formed fibrils and characterized by the low apparent half-maximal disaggregation concentration (DC50) in the range of ~22-30 μg ml⁻¹. Small-angle neutron scattering was employed to monitor the different stages of the disassembly process with respect to the size and morphology of the aggregates. Based on the obtained results a possible disassembly mechanism for amyloid fibrils interacting with fullerene/NMP complexes was proposed. The study is a principal step in understanding of the fullerenes destruction mechanism of the protein amyloids, as well as provides valuable information on how macromolecules can be engineered to disassemble unwanted amyloid aggregates by different mechanisms.
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Ebola virus (EBOV) causes severe systemic disease in humans and non-human primates characterized by high levels of viremia and virus titers in peripheral organs. The natural portals of virus entry are the mucosal surfaces and the skin where macrophages and dendritic cells (DCs) are primary EBOV targets. Due to the migratory properties of DCs, EBOV infection of these cells has been proposed as a necessary step for virus dissemination via draining lymph nodes and blood. Here we utilize chimeric mice with competent hematopoietic-driven immunity, to show that EBOV primarily infects CD11b+ DCs in non-lymphoid and lymphoid tissues, but spares the main cross-presenting CD103+ DC subset. Furthermore, depletion of CD8 and CD4 T cells resulted in loss of early control of virus replication, viremia and fatal Ebola virus disease (EVD). Thus, our findings point out at T cell function as a key determinant of EVD progress and outcome.
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The use of multivalent carbohydrate compounds to block cell-surface lectin receptors is a promising strategy to inhibit the entry of pathogens into cells and could lead to the discovery of novel antiviral agents. One of the main problems with this approach, however, is that it is difficult to make compounds of an adequate size and multivalency to mimic natural systems such as viruses. Hexakis adducts of [60] fullerene are useful building blocks in this regard because they maintain a globular shape at the same time as allowing control over the size and multivalency. Here we report water-soluble tridecafullerenes decorated with 120 peripheral carbohydrate subunits, so-called 'superballs', that can be synthesized efficiently from hexakis adducts of [60] fullerene in one step by using copper-catalysed azide-alkyne cycloaddition click chemistry. Infection assays show that these superballs are potent inhibitors of cell infection by an artificial Ebola virus with half-maximum inhibitory concentrations in the subnanomolar range.
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Unlabelled: Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family, which includes dengue, West Nile, yellow fever, and Japanese encephalitis viruses, that causes a mosquito-borne disease transmitted by the Aedes genus, with recent outbreaks in the South Pacific. Here we examine the importance of human skin in the entry of ZIKV and its contribution to the induction of antiviral immune responses. We show that human dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells are permissive to the most recent ZIKV isolate, responsible for the epidemic in French Polynesia. Several entry and/or adhesion factors, including DC-SIGN, AXL, Tyro3, and, to a lesser extent, TIM-1, permitted ZIKV entry, with a major role for the TAM receptor AXL. The ZIKV permissiveness of human skin fibroblasts was confirmed by the use of a neutralizing antibody and specific RNA silencing. ZIKV induced the transcription of Toll-like receptor 3 (TLR3), RIG-I, and MDA5, as well as several interferon-stimulated genes, including OAS2, ISG15, and MX1, characterized by strongly enhanced beta interferon gene expression. ZIKV was found to be sensitive to the antiviral effects of both type I and type II interferons. Finally, infection of skin fibroblasts resulted in the formation of autophagosomes, whose presence was associated with enhanced viral replication, as shown by the use of Torin 1, a chemical inducer of autophagy, and the specific autophagy inhibitor 3-methyladenine. The results presented herein permit us to gain further insight into the biology of ZIKV and to devise strategies aiming to interfere with the pathology caused by this emerging flavivirus. Importance: Zika virus (ZIKV) is an arbovirus belonging to the Flaviviridae family. Vector-mediated transmission of ZIKV is initiated when a blood-feeding female Aedes mosquito injects the virus into the skin of its mammalian host, followed by infection of permissive cells via specific receptors. Indeed, skin immune cells, including dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells, were all found to be permissive to ZIKV infection. The results also show a major role for the phosphatidylserine receptor AXL as a ZIKV entry receptor and for cellular autophagy in enhancing ZIKV replication in permissive cells. ZIKV replication leads to activation of an antiviral innate immune response and the production of type I interferons in infected cells. Taken together, these results provide the first general insights into the interaction between ZIKV and its mammalian host.
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Flaviviruses enter host cells by endocytosis initiated when the virus particles interact with cell surface receptors. The current model suggests that flaviviruses use at least two different sets of molecules for infectious entry: attachment factors that concentrate and/or recruit viruses on the cell surface and primary receptor(s) that bind to virions and direct them to the endocytic pathway. Here, we present the currently available knowledge regarding the flavivirus receptors described so far with specific attention to C-type lectin receptors and the phosphatidylserine receptors, T-cell immunoglobulin and mucin domain (TIM) and TYRO3, AXL and MER (TAM). Their role in flavivirus attachment and entry as well as their implication in the virus biology will be discussed in depth.
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Ligand polyvalency is a powerful modulator of protein-receptor interactions. Host-pathogen infection interactions are often mediated by glycan ligand-protein interactions, yet its interrogation with very high copy number ligands has been limited to heterogenous systems. Here we report that through the use of nested layers of multivalency we are able to assemble the most highly valent glycodendrimeric constructs yet seen (bearing up to 1,620 glycans). These constructs are pure and well-defined single entities that at diameters of up to 32 nm are capable of mimicking pathogens both in size and in their highly glycosylated surfaces. Through this mimicry these glyco-dendri-protein-nano-particles are capable of blocking (at picomolar concentrations) a model of the infection of T-lymphocytes and human dendritic cells by Ebola virus. The high associated polyvalency effects (β>10(6), β/N ~10(2)-10(3)) displayed on an unprecedented surface area by precise clusters suggest a general strategy for modulation of such interactions.
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Fullerene hexakis-adducts bearing 12 peripheral mannose moieties have been prepared by grafting sugar derivatives onto the fullerene core and assayed as inhibitors of FimH, a bacterial adhesin, using isothermal titration calorimetry, surface plasmon resonance and hemagglutination assays.
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Fullerene hexakis-adducts bearing 12 peripheral carbohydrate moieties have been prepared by grafting sugar derivatives onto the fullerene core through the copper mediated Huisgen 1,3-dipolar cycloaddition of azides and alkynes.
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Ebola virus is a highly lethal pathogen responsible for several outbreaks of hemorrhagic fever. Here we show that the primate lentiviral binding C-type lectins DC-SIGN and L-SIGN act as cofactors for cellular entry by Ebola virus. Furthermore, DC-SIGN on the surface of dendritic cells is able to function as a trans receptor, binding Ebola virus-pseudotyped lentiviral particles and transmitting infection to susceptible cells. Our data underscore a role for DC-SIGN and L-SIGN in the infective process and pathogenicity of Ebola virus infection.
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Dengue virus is a single-stranded, enveloped RNA virus that productively infects human dendritic cells (DCs) primarily at the immature stage of their differentiation. We now find that all four serotypes of dengue use DC-SIGN (CD209), a C-type lectin, to infect dendritic cells. THP-1 cells become susceptible to dengue infection after transfection of DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN), or its homologue L-SIGN, whereas the infection of dendritic cells is blocked by anti-DC-SIGN antibodies and not by antibodies to other molecules on these cells. Viruses produced by dendritic cells are infectious for DC-SIGN- and L-SIGN-bearing THP-1 cells and other permissive cell lines. Therefore, DC-SIGN may be considered as a new target for designing therapies that block dengue infection.
Article
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The dendritic cell surface receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR specifically recognize high mannose N-linked carbohydrates on viral pathogens. Previous studies have shown that these receptors bind the outer trimannose branch Manalpha1-3[Manalpha1-6]Manalpha present in high mannose structures. Although the trimannoside binds to DC-SIGN or DC-SIGNR more strongly than mannose, additional affinity enhancements are observed in the presence of one or more Manalpha1-2Manalpha moieties on the nonreducing termini of oligomannose structures. The molecular basis of this enhancement has been investigated by determining crystal structures of DC-SIGN bound to a synthetic six-mannose fragment of a high mannose N-linked oligosaccharide, Manalpha1-2Manalpha1-3[Manalpha1-2Manalpha1-6]Manalpha1-6Man and to the disaccharide Manalpha1-2Man. The structures reveal mixtures of two binding modes in each case. Each mode features typical C-type lectin binding at the principal Ca2+-binding site by one mannose residue. In addition, other sugar residues form contacts unique to each binding mode. These results suggest that the affinity enhancement displayed toward oligosaccharides decorated with the Manalpha1-2Manalpha structure is due in part to multiple binding modes at the primary Ca2+ site, which provide both additional contacts and a statistical (entropic) enhancement of binding.
Article
SWCNTs, MWCNTs and SWCNHs have been employed as virus mimicking nanocarbon platforms for the multivalent presentation of carbohydrates in an artificial Ebola virus infection model assay. These carbon nanoforms have been chemically modified by the covalent attachment of glycodendrons and glycofullerenes using the CuAAC “click chemis-try” approach. This modification dramatically increases the water solubility of these structurally different nanocarbons. Their efficiency to block DC-SIGN mediated viral infection by an artificial Ebola virus has been tested in a cellu-lar experimental assay finding that glycoconjugates based on MWCNTs functionalized with glycofullerenes are potent inhibitors of viral infection.
Article
The multivalent effect in glycosidase inhibition is a new topic in glycoscience that has emerged few years ago with the discovery of neoglycoclusters displaying strong binding enhancements over the corresponding monovalent inhibitor. Iminosugar-fullerene conjugates with high valencies have been prepared from iminosugar-terminated dendrons and a clickable fullerene hexa-adduct scaffold. The simultaneous grafting of twelve dendrons allows for a very fast dendritic growth thus limiting the number of synthetic steps required to prepare compounds with a high number of peripheral units. The grafting of first- and second-generation dendrons provided fullerodendrimers surrounded by 36 and 108 peripheral iminosugars, respectively. Inhibition studies have been carried out with a panel of glycosidases. In the particular case of Jack bean α-mannosidase, the 108-valent nanoconstruct displays inhibition in the nanomolar range and an additional binding enhancement of one order of magnitude when compared to the 36-valent analogues.
Article
Hexa-substituted fullerenes are unique scaffolds for the fast construction of globular dendrimers. Efficient synthetic methodologies based on the post-functionalization of pre-constructed fullerene hexa-adduct derivatives have been reported in recent years and dendrimers difficult or even impossible to prepare by classical fullerene chemistry are now easly accessible. Fullerodendrimers for various applications have been thus prepared. Examples include liquid crystalline materials, non-viral gene delivery systems and bioactive glycoclusters. On the other hand, fullerene hexa-adduct building blocks have been used for the ultra-fast synthesis of giant dendrimers. Indeed, the resulting dendrimers of first generation are already surrounded by 120 peripheral functional groups. This strategy has been used to prepare giant glycoclusters with anti-viral activity and multivalent glycosidase inhibitors.
Article
The high mannose structure (or its corresponding Man9 epitope) is the more abundant structure presented in pathogen envelope glycoproteins. These glycans play a key role in the pathogenesis of several pathogens and also in the communication with the immune system. Understanding the mechanism of action of these glycans requires the access to pure and chemical well-defined structures in reasonable amounts. The synthesis of these complex branched oligosaccharides is not trivial and few syntheses are described in the literature with several synthetic and purification steps and low overall yields. In this work, we described a very efficient synthetic alternative to access to this relevant Man9 epitope in a very straightforward way.
Article
An ultra-fast synthetic procedure based on the grafting of twelve fullerene macromonomers onto a fullerene hexa-adduct core has been used for the preparation of a giant molecule with 120 peripheral iminosugar residues. The inhibition profile of this giant iminosugar ball has been evaluated against various glycosidases. In the particular case of the Jack bean α-mannosidase, a dramatic enhancement of the glycosidase inhibitory effect has been evidenced for the giant molecule with 120 peripheral subunits when compared to corresponding mono- and dodecavalent model compounds.
Article
The infection of humans by lethal pathogens such as Ebola and other related viruses has not been properly addressed so far. In this context, a relevant question arises: what can chemistry do in the search for new strategies and approaches to solve this emergent problem? Although initially a variety of known chemical compounds - for other purposes - have been disappointingly tested against Ebola virus infection, more recently, specific molecules have been prepared. In this Perspective, we present a new approach directed to the design of efficient entry inhibitors to minimize the development of resistance by viral mutations. In particular, we focused on dendrimers as well as fullerene C60 - with a unique symmetrical and 3D globular structure - as biocompatible carbon platforms for the multivalent presentation of carbohydrates. The antiviral activity of these compounds in an Ebola pseudotyped infection model were in the low micromolar range for fullerenes with 12 and 36 mannoses. However, new tridecafullerenes - in which the central alkyne scaffold of [60]fullerene has been connected to 12 sugar-containing [60]fullerene units (total 120 mannoses)- exhibit an outstanding antiviral activity with IC50 in the subnanomolar range! The multivalent presentation of specific carbohydrates by using 3D fullerenes as controlled biocompatible carbon scaffolds represents a real advance being currently the most efficient molecules in vitro against Ebola virus infection. However, additional studies are needed to determine the optimized fullerene-based leads for practical applications.
Article
The last years have witnessed an impressive development of material sciences following the burst of nanotechnology, which has greatly contributed to the development of nonviral gene delivery systems with improved properties for the efficient transport of nucleic acid payloads for gene therapy purposes. In spite of intense efforts, emulating the transfecting capabilities of viruses with synthetic systems represents an extraordinary challenge still far from accomplishment. Achieving this goal requires general and flexible approaches allowing the construction of appropriate carriers and the elucidation of the key rules governing their capacity to supramolecularly interact with nucleic acids and mediate its active transport/delivery through biological membranes. Molecular nano-objects exhibiting persistent shape- and volume, termed “molecular nanoparticles (MNPs)”, in combination with diversity-oriented precise macromolecular chemistry, offers excellent opportunities towards these goals by enabling the preorganization of functional elements, the generation of libraries of discrete architectures and the implementation of structure/activity relationship studies. The body of work on cyclodextrin, calixarene, pillarene, fullerene, macrocyclic peptide and cyclotrehalan platforms here reviewed illustrates the potential of the MNP concept to produce single isomer constructs that can be programmed to mediate the safe delivery of nucleic acids to the target cells.
Article
Background To estimate the frequency and duration of detectable Zika virus (ZIKV) RNA in human body fluids, we prospectively assessed a cohort of newly infected participants in Puerto Rico. Methods We evaluated samples obtained from 150 participants (including 55 men) in whom ZIKV RNA was detected on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay in urine or blood in an enhanced arboviral clinical surveillance site. We collected serum, urine, saliva, semen, and vaginal secretions weekly for the first month and then at 2, 4, and 6 months. All specimens were tested by means of RT-PCR, and serum was tested with the use of anti–ZIKV IgM enzyme-linked immunosorbent assay. Among the participants with ZIKV RNA in any specimen at week 4, biweekly collection continued until all specimens tested negative. We used parametric Weibull regression models to estimate the time until the loss of ZIKV RNA detection in each body fluid and reported the findings in medians and 95th percentiles. Results The medians and 95th percentiles for the time until the loss of ZIKV RNA detection were 14 days (95% confidence interval [CI], 11 to 17) and 54 days (95% CI, 43 to 64), respectively, in serum; 8 days (95% CI, 6 to 10) and 39 days (95% CI, 31 to 47) in urine; and 34 days (95% CI, 28 to 41) and 81 days (95% CI, 64 to 98) in semen. Few participants had detectable ZIKV RNA in saliva or vaginal secretions. Conclusions The prolonged time until ZIKV RNA clearance in serum in this study may have implications for the diagnosis and prevention of ZIKV infection. Current sexual-prevention guidelines recommend that men use condoms or abstain from sex for 6 months after ZIKV exposure; in 95% of the men in this study, ZIKV RNA was cleared from semen after about 3 months. (Funded by the Centers for Disease Control and Prevention.)
Article
Zika virus has rapidly spread reaching a global distribution pattern similar to that of dengue virus, and has been associated with serious neurological and developmental pathologies, like congenital malformation during pregnancy and Guillain-Barré syndrome. Sequence analysis of different clinical and laboratory isolates has shown the existence of mutants with loss of the conserved N-glycosylation motif on domain I of protein E that is common to all flaviviruses. We found that loss of E N-linked glycosylation leads to compromised expression and secretion of E ectodomain from mammalian cells. For both, wild type and glycosylation-negative mutant, secretion was independent of co-expression of the PrM viral protein, but highly dependent on temperature. Low temperature (28 °C) favoured secretion, although the glycosylation mutant E ectodomain showed impaired secretion and membrane display compared to the wild type. Production of pseudoviral particles with a West Nile virus replicon packaged with the Zika virus structural proteins C-PrM-E was significantly reduced with the non-glycosylated E. Similarly, glycosylation-negative pseudoviral particles showed impaired infectivity of Vero cells and reduced ability to infect K562 cells upon particles opsonisation with anti-E antibodies.
Article
The World Health Organization recently announced that the Zika epidemic is no longer a Public Health Emergency of International Concern, a designation reserved for acute threats that Zika received in February. But the decision only means that Zika has evolved from an emergency to another long-term public health challenge. The Zika virus is now firmly entrenched in Latin America, which is already battling several other mosquito-borne diseases. Meanwhile, Zika vaccines aren't available yet, and fundamental gaps remain in scientists' knowledge of the virus and the risk of microcephaly and other birth defects that it poses. Perhaps the biggest question is also the most difficult to answer: Why have the effects of Zika been so pronounced in northeastern Brazil?
Article
In this feature article we discuss the particular relevance of glycans as components or targets of functionalized nanoparticles (NPs) for potential applications in personalized medicine but we will not enter into descriptions for their preparation. For a more general view covering the preparation and applications of glyconanomaterials the reader is referred to a number of recent reviews. The combination of glyco- and nanotechnology is already providing promising new tools for more personalized solutions to diagnostics and therapy. Current applications relevant to personalized medicine include drug targeting, localized radiation therapy, imaging of glycan expression of cancer cells, point of care diagnostics, cancer vaccines, photodynamic therapy, biosensors, and glycoproteomics.
Article
The synthesis of unprecedented multimeric Kdo glycoclusters based on fullerene and calix[4]arene central scaffolds is reported. The compounds were used to study the mechanism and scope of multivalent glycosyltransferase inhibition. Multimeric mannosides based on porphyrin and pillar[5]arenes were also generated in a controlled manner. Twelve glycoclusters and their monomeric ligands were thus assayed against heptosyltransferase WaaC, which is an important bacterial glycosyltransferase that is involved in lipopolysaccharide biosynthesis. It was first found that all the multimers interact solely with the acceptor binding site of the enzyme even when the multimeric ligands mimic the heptose donor. Second, the novel Kdo glycofullerenes displayed very potent inhibition (Ki=0.14 μm for the best inhibitor); an inhibition level rarely observed with glycosyltransferases. Although the observed “multivalent effects” (i.e., the enhancement of affinity of a ligand when presented in a multimeric fashion) were in general modest, a dramatic effect of the central scaffold on the inhibition level was evidenced: the fullerene and the porphyrin scaffolds being by far superior to the calix- and pillar-arenes. We could also show, by dynamic light scattering analysis, that the best inhibitor had the propensity to form aggregates with the heptosyltransferase. This aggregative property may contribute to the global multivalent enzyme inhibition, but probably do not constitute the main origin of inhibition.
Article
The synthesis of a new highly symmetric hexakis adduct of C60 appended with 12 cyclooctyne moieties has been carried out. This compound has been used for the copper-free strain-promoted cycloaddition reaction to a series of azides with excellent yields. This strategy for the obtention of clicked adducts of [60]fullerene is of special interest for biological applications.
Article
Glycosidases are key enzymes in metabolism, pathogenic/antipathogenic mechanisms and normal cellular functions. Recently, a novel approach for glycosidase inhibition that conveys multivalent glycomimetic conjugates has emerged. Many questions regarding the mechanism(s) of multivalent enzyme inhibition remain unanswered. Herein we report the synthesis of a collection of novel homo- and heterovalent glyco(mimetic)-fullerenes purposely conceived for probing the contribution of non-catalytic pockets in glysosidases to the multivalent inhibitory effect. Their affinities towards selected glycosidases were compared with data from homovalent fullerene conjugates. An original competitive glycosidase-lectin binding assay demonstrated that the multivalent derivatives and the substrate compete for low affinity non-glycone binding sites of the enzyme, leading to inhibition by a "recognition and blockage" mechanism. Most notably, this work provides evidence for enzyme inhibition by multivalent glycosystems, which will likely have a strong impact in the glycosciences given the utmost relevance of multivalency in Nature.
Article
Interfacial multivalent interactions at pathogen-cell interfaces can be competitively inhibited by multivalent scaffolds that prevent pathogen adhesion to the cells during the initial stages of infection. The lack of understanding of complex biological systems makes the design of an efficient multivalent inhibitor a toilsome task.Therefore, we have highlighted the main issues and concerns associated with pathogen inhibition at interfaces, which are dependent on the nature and properties of both multivalent inhibitors and pathogens, such as viruses and bacteria. The challenges associated with different cores or carrier scaffolds of multivalent inhibitors are concisely discussed with selected examples.
Article
A fullerene hexa-adduct building block bearing an azide functionality was prepared in six steps, and grafted onto a central fullerene core under copper-catalyzed azide-alkyne cycloaddition conditions. The resulting tridecafullerene derivative is a first generation dendrimer with 132 peripheral ethyl ester groups. This compound was characterized by different spectroscopic techniques (1H and 13C NMR, IR, UV/Vis), and by MALDI-TOF mass spectrometry. Despite a high degree of fragmentation, the molecular-ion peak was detected, and all the observed fragments originate from a fully clicked derivative. This shows that the construction of dendrimers in a single dendritic growth step from fullerene hexa-adduct macromonomers is an efficient strategy to produce monodisperse compounds.
Article
Zika virus is rapidly spreading throughout the Americas and the Caribbean. The association with microcephaly has led the WHO to declare a public health emergency. This review describes our current understanding of the characteristics of Zika virus infection.
Article
α(1,2)mannobiosides with different substituents at the reducing end have been synthesized by a common strategy using benzoyls as permanent protecting groups and an acetyl as orthogonal protecting group at position C2 of the glycosyl acceptor. The new synthetic strategy has been performed reducing remarkably the number of purification steps, the time of the synthesis (less than 72 hours) and improving the overall yield at least three times respect to the best procedure described in the literature at the moment. Additionally, this protecting group strategy is compatible with the presence of azido groups and the use of the Cu catalyzed azide alkyne cicloaddiction (CuAAC) also called “click chemistry” to conjugate the α(1-2)mannobiosides to different scaffolds for the preparation of mannosyl multivalent systems.
Article
Multivalent nanoconstructs, extensively used for enhancing the recognition of biomolecular targets, have been recently exploited for enzyme inhibition showing interesting properties such as improvement of inhibitory potency and selectivity. We review herein the recent results highlighting the potential of multivalent nanoconstructs for the inhibition of different enzymes, and the emerging trends in the generation and identification of multivalent clusters as enzyme inhibitors.
Article
A series of water-soluble glycofullerenes containing up to 24 fucose residues have been prepared. These compounds were tested against the two bacterial fucose-binding lectins LecB and RSL, and bearing 24 fucose residues appeared to be the best known inhibitor of both lectins to date. We have shown that increasing both the valency and the length of the spacer between the central core and the peripheral sugars can be beneficial for the affinity.
Article
Interacting biomolecules form complex and dynamic information networks that can be understood thanks to thermodynamic and kinetics fundamental principles. The simplest way to represent such an interaction is to consider two biomolecules in dynamic association following Fisher's lock-key concept, the resulting complex being more stable than the two separated biomolecules. The high diversity of lectin structures and functions and the relatively low number of monosaccharidic bricks may, at first, appear contradictory. The discovery of lectins in all living organisms highlights an old evolutionary onset, thus triggering an increasing interest regarding their roles. Even though plant lectins were the first identified, their functions are not really well-understood yet. They are mostly proposed to be involved in defense mechanisms against parasites, fungi, and predators and in nitrogen fixation through the plant-rhizobium symbiosis.
Article
Click reactions largely cross the borders of organic synthetic chemistry and are now at the forefront of many interdisciplinary studies at the interfaces between chemistry, physics, and biology. As part of this research, our group is involved in a program on the development of clickable fullerene building blocks and their application in the preparation of a large variety of new advanced materials and bioactive compounds. Importantly, the introduction of the click chemistry concept in fullerene chemistry allowed us to produce compounds that would barely be accessible by using the classical tools of fullerene chemistry. This is particularly the case for the conjugation of fullerenes with other carbon nanoforms, such as carbon nanohorns and graphene. It is also the case for most of the sophisticated molecular ensembles constructed from clickable fullerene hexa-adduct building blocks. In this paper, we have summarized our ongoing progress in this particular field. Dedicated to Professor Fernando Langa on the occasion of his 60th birthday.
Article
DC-SIGN is a C-type lectin receptor on antigen presenting cells (dendritic cells) which has an important role in some viral infection, notably by HIV and Dengue virus (DV). Multivalent presentation of carbohydrates on dendrimeric scaffolds has been shown to inhibit DC-SIGN binding to HIV envelope glycoprotein gp120, thus blocking viral entry. This approach has interesting potential applications for infection prophylaxis. In an effort to develop high affinity inhibitors of DC-SIGN mediated viral entry, we have synthesized a group of glycodendrimers of different valency that bear different carbohydrates or glycomimetic DC-SIGN ligands and have studied their DC-SIGN binding activity and antiviral properties both in an HIV and a Dengue infection model. Surface Plasmon Resonance (SPR) competition studies have demonstrated that the materials obtained bind efficiently to DC-SIGN with IC50s in the μm range, which depend on the nature of the ligand and on the valency of the scaffold. In particular, a hexavalent presentation of the DC-SIGN selective antagonist 4 displayed high potency, as well as improved accessibility and chemical stability relative to previously reported dendrimers. At low μm concentration the material was shown to block both DC-SIGN mediated uptake of DV by Raji cells and HIV trans-infection of T cells.
Article
In genital mucosa, different fates are described for HIV according to the sub-type of dendritic cells (DCs) involved in its recognition. This notably depends on the C-type lectin receptor, langerin or DC-SIGN, involved in gp120 interaction. Langerin blocks HIV transmission by its internalization in specific organelles of Langerhans cells. On the contrary DC-SIGN enhances HIV trans-infection of T lymphocytes. Thus, approaches aiming to inhibit DC-SIGN, without blocking langerin, represent attractive anti-HIV strategies. We previously demonstrated that dendrons bearing multiple copies of glycomimetic compounds were able to block DC-SIGN-dependent HIV infection in cervical explant models. Optimization of such ligand requires detailed characterization of its binding mode. In the present work we determined the first high-resolution structure of a glycomimetic/DC-SIGN complex by X-ray crystallography. This glycomimetic, pseudo-1,2-mannobioside, shares shape and conformational properties with Manα1-2Man, its natural counterpart. However, it uses the binding epitope previously described for Lewis X, a ligand specific for DC-SIGN among the C-type lectin family. Thus, selectivity gain for DC-SIGN vs langerin is observed with pseudo-1,2-mannobioside as shown by surface plasmon resonance analysis. In parallel, ligand binding was also analyzed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol. These studies demonstrate that the complex, defined by X-ray crystallography, represents the unique binding mode of this ligand as opposed to the several binding orientations described for the natural ligand. This exclusive binding mode and its selective interaction properties position this glycomimetic as a good lead compound for rational improvement based on a structurally driven approach.