Antiviral Targets and Strategies to Treat and Prevent Human Norovirus Infections

Human norovirus (HuNoV) is the leading cause of nonbacterial gastroenteritis worldwide with the GII.4 genotype accounting for over 80% of infections. The major capsid protein of GII.4 variants is evolving rapidly, resulting in new epidemic variants with altered antigenic potentials that must be considered for the development of an effective vaccine. In this study, we identify and characterize linear blockade B-cell epitopes in HuNoV GII.4. Five unique linear B-cell epitopes, namely P2A, P2B, P2C, P2D, and P2E, were predicted on the surface-exposed regions of the capsid protein. Evolving of the surface-exposed epitopes over time was found to correlate with the emergence of new GII.4 outbreak variants. Molecular dynamic simulation (MD) analysis and molecular docking revealed that amino acid substitutions in the putative epitopes P2B, P2C, and P2D could be associated with immune escape and the appearance of new GII.4 variants by affecting solvent accessibility and flexibility of the antigenic sites and histo-blood group antigens (HBAG) binding. Testing the synthetic peptides in wild-type mice, epitopes P2B (336–355), P2C (367–384), and P2D (390–400) were recognized as GII.4-specific linear blockade epitopes with the blocking rate of 68, 55 and 28%, respectively. Blocking rate was found to increase to 80% using the pooled serum of epitopes P2B and P2C. These data provide a strategy for expanding the broad blockade potential of vaccines for prevention of NoV infection.

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Experimental miniature piglet model for the infection of human norovirus GII

Journal of Medical Virology ◽

10.1002/jmv.24991 ◽

2017 ◽

Vol 90 (4) ◽

pp. 655-662 ◽

Cited By ~ 13

Author(s):

Dong Joo Seo ◽

Day Jung ◽

Soontag Jung ◽

Seung-Kwon Ha ◽

Sang-Do Ha ◽

...

Keyword(s):

Human Norovirus ◽

Norovirus Gii

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Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets

Science ◽

10.1126/science.abi5224 ◽

2021 ◽

pp. eabi5224

Author(s):

Nunziata Maio ◽

Bernard A. P. Lafont ◽

Debangsu Sil ◽

Yan Li ◽

J. Martin Bollinger ◽

...

Keyword(s):

Rna Polymerase ◽

Metal Binding ◽

Rna Dependent Rna Polymerase ◽

Iron Sulfur Clusters ◽

Metal Binding Sites ◽

Iron Sulfur ◽

Cryo Electron Microscopy ◽

Metal Cofactors ◽

Antiviral Targets ◽

Viral Helicase

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp, nsp12, ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly, potently inhibited the RdRp, and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19.

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The Pleiotropic Function of Human Sirtuins as Modulators of Metabolic Pathways and Viral Infections

Cells ◽

10.3390/cells10020460 ◽

2021 ◽

Vol 10 (2) ◽

pp. 460

Author(s):

Mohammed Hamed Alqarni ◽

Ahmed Ibrahim Foudah ◽

Magdy Mohamed Muharram ◽

Nikolaos E. Labrou

Keyword(s):

Metabolic Pathways ◽

Histone Deacetylases ◽

Viral Infections ◽

Cell Physiology ◽

Functional Roles ◽

Regulatory Processes ◽

Complex Functions ◽

Natural Polyphenol ◽

Antiviral Targets

Sirtuins (SIRTs) are nicotinamide adenine dinucleotide-dependent histone deacetylases that incorporate complex functions in the mechanisms of cell physiology. Mammals have seven distinct members of the SIRT family (SIRT1-7), which play an important role in a well-maintained network of metabolic pathways that control and adapt the cell to the environment, energy availability and cellular stress. Until recently, very few studies investigated the role of SIRTs in modulating viral infection and progeny. Recent studies have demonstrated that SIRT1 and SIRT2 are promising antiviral targets because of their specific connection to numerous metabolic and regulatory processes affected during infection. In the present review, we summarize some of the recent progress in SIRTs biochemistry and their emerging function as antiviral targets. We also discuss the potential of natural polyphenol-based SIRT modulators to control their functional roles in several diseases including viral infections.

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Fucoidan But Not 2′-Fucosyllactose Inhibits Human Norovirus Replication in Zebrafish Larvae

Viruses ◽

10.3390/v13030461 ◽

2021 ◽

Vol 13 (3) ◽

pp. 461

Author(s):

Malcolm Turk Hsern Tan ◽

Yan Li ◽

Mohamad Eshaghi Gorji ◽

Zhiyuan Gong ◽

Dan Li

Keyword(s):

Brown Algae ◽

Disease Burden ◽

Type A ◽

Fucus Vesiculosus ◽

Human Norovirus ◽

Human Noroviruses ◽

Molecular Weights ◽

Zebrafish Larvae ◽

Virus Like Particle

Human noroviruses (hNoVs) cause heavy disease burden worldwide and there is no clinically approved vaccination or antiviral hitherto. In this study, with the use of a zebrafish larva in vivo platform, we investigated the anti-hNoV potentials of fucoidan (from brown algae Fucus vesiculosus) and 2′-Fucosyllactose (2′-FL). As a result, although both fucoidan and 2′-FL were able to block hNoV GII.4 virus-like particle (VLPs) from binding to type A saliva as expected, only fucoidan, but not 2′-FL, was able to inhibit the replication of hNoV GII.P16-GII.4 in zebrafish larvae, indicating the possible needs of higher molecular weights for fucosylated carbohydrates to exert anti-hNoV effect.

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Antiviral Resistance against Viral Mutation: Praxis and Policy for SARS-CoV-2

Computational and Mathematical Biophysics ◽

10.1515/cmb-2020-0119 ◽

2021 ◽

Vol 9 (1) ◽

pp. 81-89

Author(s):

Robert Penner

Keyword(s):

Free Energy ◽

Vaccine Development ◽

A Priori ◽

Structural Data ◽

Medical Sciences ◽

Spike Glycoprotein ◽

Mutagenic Potential ◽

Viral Mutation ◽

Novel Method ◽

Antiviral Targets

Abstract Tools developed by Moderna, BioNTech/Pfizer, and Oxford/Astrazeneca, among others, provide universal solutions to previously problematic aspects of drug or vaccine delivery, uptake and toxicity, portending new tools across the medical sciences. A novel method is presented based on estimating protein backbone free energy via geometry to predict effective antiviral targets, antigens and vaccine cargos that are resistant to viral mutation. This method is reviewed and reformulated in light of the recent proliferation of structural data on the SARS-CoV-2 spike glycoprotein and its mutations in multiple lineages. Key findings include: collections of mutagenic residues reoccur across strains, suggesting cooperative convergent evolution; most mutagenic residues do not participate in backbone hydrogen bonds; metastability of the glyco-protein limits the change of free energy through mutation thereby constraining selective pressure; and there are mRNA or virus-vector cargos targeting low free energy peptides proximal to conserved high free energy peptides providing specific recipes for vaccines with greater specificity than the full-spike approach. These results serve to limit peptides in the spike glycoprotein with high mutagenic potential and thereby provide a priori constraints on viral and attendant vaccine evolution. Scientific and regulatory challenges to nucleic acid therapeutic and vaccine development and deployment are finally discussed.

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