Investigation of N Terminal Domain of SARS CoV 2 Nucleocapsid Protein with Antiviral Compounds Based on Molecular Modeling Approach

Mapping Intimacies ◽

10.14293/s2199-1006.1.sor-.pppt99i.v1 ◽

2020 ◽

Author(s):

Gizem Tatar ◽

Kemal Turhan

Keyword(s):

Rna Binding ◽

Antiviral Agents ◽

Antiviral Drug ◽

Md Simulations ◽

Inhibition Mechanism ◽

Ligand Complex ◽

N Protein ◽

Antiviral Compounds ◽

Recent Outbreak ◽

Human Infections

The recent outbreak of coronavirus disease (COVID-19) in China caused by SARS-CoV-2 virus continually lead to worldwide human infections and deaths. It is currently no specific viral protein targeted therapeutics yet. The nucleocapsid (N) protein of coronaviruses (CoVs) is a multifunctional RNA-binding protein necessary for viral RNA replication and transcription. Therefore, it is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. Herein, we focus here on the potential to repurpose antiviral compounds approved or in development for treating infections caused by human CoVs. For this purpose, we used the docking methodology to better understand the inhibition mechanism of SARS-CoV-2 N protein with this existing 34 antiviral compounds. The results of this analysis were showed that Nafamostat, Rapamycin, Saracatinib, Imatinib and Camostat are the top hit compounds with binding energy (-10.24 kcal/mol, -9.88 kcal/mol, -9.66 kcal/mol, -9.23 kcal/mol, -9.07 kcal/mol) and K i (0.0313 mM, 0.05736 mM, 0.08304 mM, 0.17224 mM, 0.22413 mM). In addition, this analysis also showed that the most common residues that interact with the compounds are Lys65, Phe66, Arg 68, Glu69, Tyr123, Gly124, Lys127, Ile 130, Val133 and Ala134. These results suggest that these residues are potential drug targeting sites for the SARS-CoV-2 N protein. Subsequently, protein-ligand complex stability was examined with Molecular Dynamics (MD) simulations for the Nafamostat compound, which showed the best binding affinity. According to the results of this study, the interaction between the compound and the crucial residues of the target were maintained. Based on this information, we propose guidelines to develop novel N protein-based antiviral agents that target CoVs.

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ANTIVIRAL PROPERTIES OF MICROALGAE AND CYANOBACTERIA

Journal of Experimental Biology and Agricultural Sciences ◽

10.18006/2021.9(spl-1-gcsgd_2020).s43.s48 ◽

2021 ◽

Vol 9 (Spl-1- GCSGD_2020) ◽

pp. S43-S48

Author(s):

Manishaa Sri Mahendran ◽

◽

Sinouvassane Djearamane ◽

Ling Shing Wong ◽

Govindaraju Kasivelu ◽

...

Keyword(s):

Viral Infections ◽

Virus Disease ◽

Antiviral Agents ◽

Freshwater Microalgae ◽

Algal Biotechnology ◽

Antiviral Compounds ◽

Recent Outbreak ◽

Respiratory Treatment ◽

Algal Polysaccharides ◽

Methods Of Treatment

The recent outbreak of Corona Virus Disease (COVID-19) and the surge in accelerating the development of a vaccine to fight against the SARS-CoV-2 virus has imposed greater challenges to humanity worldwide. There is lack of research into the production of effective vaccines and methods of treatment against viral infections. As of now, strategies encompassing antiviral drugs and corticosteroids alongside mechanical respiratory treatment are in practice as frontline treatments. Though studies have reported that microalgae possess antiviral properties, only a few cases have presented the existence of antiviral compounds such as algal polysaccharides, lectins, aggluttinins, scytovirin, algal lipids such as sulfoquinovosyldiacylglycerol (SQDG), monogalactosyldiacylglycerides (MGDG) and digalactosyldiacylglycerides (DGDG), and algal biopigments especially chlorophyll analogues, marennine, phycobiliproteins, phycocyanin, phycoerythrin and allophycocyanin that are derived from marine and freshwater microalgae. Given the chemodiversity of bioactive compounds from microalgae and the present scenario, algal biotechnology is seen as a prospective source of antiviral and anti-inflammatory compounds that can be used to develop antiviral agents. Microalgae with potential as antivirals and microalgae derived functional compounds to treat viral diseases are summarized and can be used as a reference in developing algae-derived antivirals to treat SARS-CoV-2 and other similar viruses.

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Druggability for COVID19 – in Silico Discovery of Potential Drug Compounds Against Nucleocapsid (N) Protein of SARS-CoV-2

10.26434/chemrxiv.12387290 ◽

2020 ◽

Author(s):

Manisha Ray ◽

Saurav Sarkar ◽

Surya Narayan Rath

Keyword(s):

Rna Binding ◽

Vaccine Development ◽

Antiviral Drug ◽

Sequence Divergence ◽

Binding Affinities ◽

Potential Drug ◽

Mortality And Morbidity ◽

N Protein ◽

Drug Compounds ◽

Drug Compound

Background: The coronavirus disease 2019 (COVID-19) was caused havoc throughout the world by creating widespread mortality and morbidity. The presence of RNA binding domain in the nucleocapsid (N) protein of SARS-CoV-2 is a potential drug target, serving multiple critical functions during the viral life cycle, especially the viral replication. The unavailability of vaccines and proper antiviral drugs encourages the researchers to identify some potential antiviral drug compounds to be used against N protein of SARS-CoV-2 for this current scenario. While vaccine development might take some time, the identification of a drug compound might decrease the widespread deaths and suffering. Method: This study was analyzed the phylogenetic relationship of N protein sequence divergence with other 49 CoV species and also identified the conserved regions according to protein families through conserved domain search. Along with it, good structural binding affinities of some natural/synthetic phytocompounds/ drugs against N protein were also found using the molecular docking approaches. Result: The analyzed antiviral properties, predicted binding affinities and the presence of higher numbers of Hydrogen bonds of selected compounds represent the drug-ability of these compounds. Among them, the established antiviral drug Glycyrrhizic acid and the phytochemical Theaflavin can be considered as putative drug compound against target protein of SARS-CoV-2 as they showed all the properties of a potential drug. Conclusion: The findings of this study might lead to the development of a drug for the disease and helpful to reduce the risk of deadly infections in host cell due to SARS-CoV-2.

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Antiviral Compounds from Myxobacteria

Microorganisms ◽

10.3390/microorganisms6030073 ◽

2018 ◽

Vol 6 (3) ◽

pp. 73 ◽

Cited By ~ 5

Author(s):

Lucky Mulwa ◽

Marc Stadler

Keyword(s):

Broad Spectrum ◽

Viral Infections ◽

Antiviral Agents ◽

Antiviral Drug ◽

Public Health Issue ◽

Target Cells ◽

Global Public Health ◽

Drug Candidates ◽

Antiviral Compounds ◽

Spectrum Activity

Viral infections including human immunodeficiency virus (HIV), cytomegalovirus (CMV), hepatitis B virus (HBV), and hepatitis C virus (HCV) pose an ongoing threat to human health due to the lack of effective therapeutic agents. The re-emergence of old viral diseases such as the recent Ebola outbreaks in West Africa represents a global public health issue. Drug resistance and toxicity to target cells are the major challenges for the current antiviral agents. Therefore, there is a need for identifying agents with novel modes of action and improved efficacy. Viral-based illnesses are further aggravated by co-infections, such as an HIV patient co-infected with HBV or HCV. The drugs used to treat or manage HIV tend to increase the pathogenesis of HBV and HCV. Hence, novel antiviral drug candidates should ideally have broad-spectrum activity and no negative drug-drug interactions. Myxobacteria are in the focus of this review since they produce numerous structurally and functionally unique bioactive compounds, which have only recently been screened for antiviral effects. This research has already led to some interesting findings, including the discovery of several candidate compounds with broad-spectrum antiviral activity. The present review looks at myxobacteria-derived antiviral secondary metabolites.

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Druggability for COVID19 – in Silico Discovery of Potential Drug Compounds Against Nucleocapsid (N) Protein of SARS-CoV-2

10.26434/chemrxiv.12387290.v1 ◽

2020 ◽

Author(s):

Manisha Ray ◽

Saurav Sarkar ◽

Surya Narayan Rath

Keyword(s):

Rna Binding ◽

Vaccine Development ◽

Antiviral Drug ◽

Sequence Divergence ◽

Binding Affinities ◽

Potential Drug ◽

Mortality And Morbidity ◽

N Protein ◽

Drug Compounds ◽

Drug Compound

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SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and alters gene expression via direct interaction with host mRNAs

10.1101/2020.10.23.342113 ◽

2020 ◽

Cited By ~ 2

Author(s):

Syed Nabeel-Shah ◽

Hyunmin Lee ◽

Nujhat Ahmed ◽

Edyta Marcon ◽

Shaghayegh Farhangmehr ◽

...

Keyword(s):

Gene Expression ◽

Rna Binding ◽

Antiviral Drug ◽

Ectopic Expression ◽

Stress Granule ◽

Hek293 Cells ◽

Physical Interaction ◽

Granule Formation ◽

N Protein ◽

Target Mrnas

AbstractThe COVID-19 pandemic has caused over one million deaths thus far. There is an urgent need for the development of specific viral therapeutics and a vaccine. SARS-CoV-2 nucleocapsid (N) protein is highly expressed upon infection and is essential for viral replication, making it a promising target for both antiviral drug and vaccine development. Here, starting from a functional proteomics workflow, we initially catalogued the protein-protein interactions of 21 SARS-CoV-2 proteins in HEK293 cells, finding that the stress granule resident proteins G3BP1 and G3BP2 copurify with N with high specificity. We demonstrate that N protein expression in human cells sequesters G3BP1 and G3BP2 through its physical interaction with these proteins, attenuating stress granule (SG) formation. The ectopic expression of G3BP1 in N-expressing cells was sufficient to reverse this phenotype. Since N is an RNA-binding protein, we performed iCLIP-sequencing experiments in cells, with or without exposure to oxidative stress, to identify the host RNAs targeted by N. Our results indicate that SARS-CoV-2 N protein binds directly to thousands of mRNAs under both conditions. Like the G3BPs stress granule proteins, N was found to predominantly bind its target mRNAs in their 3’UTRs. RNA sequencing experiments indicated that expression of N results in wide-spread gene expression changes in both unstressed and oxidatively stressed cells. We suggest that N regulates host gene expression by both attenuating stress granules and binding directly to target mRNAs.

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Benzothiazole moieties and their derivatives as antimicrobial and antiviral agents: A mini-review

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11i3.2459 ◽

2020 ◽

Vol 11 (3) ◽

pp. 3309-3315

Author(s):

Manahil B Elamin ◽

Amani Abd Elrazig Salman Abd Elaziz ◽

Emad Mohamed Abdallah

Keyword(s):

Scientific Literature ◽

Antiviral Agents ◽

Antiviral Drug ◽

Pharmaceutical Chemistry ◽

Heterocyclic Chemistry ◽

Antimicrobial Drugs ◽

Benzothiazole Derivatives ◽

Global Concern ◽

Pharmaceutical Molecules ◽

Heterocyclic Moiety

Heterocyclic chemistry has provided an inexhaustible source of pharmaceutical molecules. Heterocyclic compounds such as benzothiazole moieties and its derivatives area substantial class of compounds in pharmaceutical chemistry and exhibited therapeutic capabilities, such as antitumor, anticancer, antioxidant, antidiabetic, antiviral, antimicrobial, antimalarial, anthelmintic and other activities. Besides, some antibiotics such as penicillin and cephalosporin have heterocyclic moiety. The growing prevalence of multi-drug resistant pathogens represents serious global concern,which requires the development of new antimicrobial drugs. Moreover, the emergence of pandemic SARSCoV-2 causing Covid-19 disease and all these health dilemmas urge the scientific community to examine the possible antimicrobial and antiviral capacities of some bioactive benzothiazole derivatives against these severe causative agents.This mini-review highlights some recent scientific literature on different benzothiazole molecules and their derivatives. It turns out that, there are numerous synthesized benzothiazole derivatives which exhibited different mode of actions against microorganisms or viruses and accordingly suggested them as an active candidate in the discovery of new antimicrobial or antiviral agents for clinical development. The recommended bioactive benzothiazole derivatives mentioned in the current study are mainly Schiff bases, azo dyes and metal complexes benzothiazole derivatives; the starting material for most of these derivatives are 2-aminobenzothiazole although careful pharmaceutical studies should be conducted to ensure the safety and efficacy of these bioactive synthesized molecules as an antimicrobial or antiviral drug in the future.

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Nitrogen-Based Heterocyclic Compounds: A Promising Class of Antiviral Agents against Chikungunya Virus

Life ◽

10.3390/life11010016 ◽

2020 ◽

Vol 11 (1) ◽

pp. 16

Author(s):

Andreza C. Santana ◽

Ronaldo C. Silva Filho ◽

José C. J. M. D. S. Menezes ◽

Diego Allonso ◽

Vinícius R. Campos

Keyword(s):

Antiviral Activity ◽

Mechanism Of Action ◽

Heterocyclic Compounds ◽

Chikungunya Virus ◽

Antiviral Agents ◽

Antiviral Drug ◽

Important Class ◽

Available Nitrogen ◽

Global Threat ◽

Present Understanding

Arboviruses, in general, are a global threat due to their morbidity and mortality, which results in an important social and economic impact. Chikungunya virus (CHIKV), one of the most relevant arbovirus currently known, is a re-emergent virus that causes a disease named chikungunya fever, characterized by a severe arthralgia (joint pains) that can persist for several months or years in some individuals. Until now, no vaccine or specific antiviral drug is commercially available. Nitrogen heterocyclic scaffolds are found in medications, such as aristeromycin, favipiravir, fluorouracil, 6-azauridine, thioguanine, pyrimethamine, among others. New families of natural and synthetic nitrogen analogous compounds are reported to have significant anti-CHIKV effects. In the present work, we focus on these nitrogen-based heterocyclic compounds as an important class with CHIKV antiviral activity. We summarize the present understanding on this class of compounds against CHIKV and also present their possible mechanism of action.

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Amantadine Inhibits SARS-CoV-2 In Vitro

Viruses ◽

10.3390/v13040539 ◽

2021 ◽

Vol 13 (4) ◽

pp. 539

Author(s):

Klaus Fink ◽

Andreas Nitsche ◽

Markus Neumann ◽

Marica Grossegesse ◽

Karl-Heinz Eisele ◽

...

Keyword(s):

Influenza A ◽

Antiviral Agents ◽

Antiviral Drug ◽

Systemic Exposure ◽

Topical Administration ◽

Counter Measures ◽

Travel Restrictions ◽

Drug Treatments ◽

Intranasal Instillation

Since the SARS-CoV-2 pandemic started in late 2019, the search for protective vaccines and for drug treatments has become mandatory to fight the global health emergency. Travel restrictions, social distancing, and face masks are suitable counter measures, but may not bring the pandemic under control because people will inadvertently or at a certain degree of restriction severity or duration become incompliant with the regulations. Even if vaccines are approved, the need for antiviral agents against SARS-CoV-2 will persist. However, unequivocal evidence for efficacy against SARS-CoV-2 has not been demonstrated for any of the repurposed antiviral drugs so far. Amantadine was approved as an antiviral drug against influenza A, and antiviral activity against SARS-CoV-2 has been reasoned by analogy but without data. We tested the efficacy of amantadine in vitro in Vero E6 cells infected with SARS-CoV-2. Indeed, amantadine inhibited SARS-CoV-2 replication in two separate experiments with IC50 concentrations between 83 and 119 µM. Although these IC50 concentrations are above therapeutic amantadine levels after systemic administration, topical administration by inhalation or intranasal instillation may result in sufficient amantadine concentration in the airway epithelium without high systemic exposure. However, further studies in other models are needed to prove this hypothesis.

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The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

Nature Communications ◽

10.1038/s41467-020-20768-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Shan Lu ◽

Qiaozhen Ye ◽

Digvijay Singh ◽

Yong Cao ◽

Jolene K. Diedrich ◽

...

Keyword(s):

Phase Separation ◽

Potential Role ◽

Rna Binding ◽

Stress Granule ◽

M Protein ◽

Rich Region ◽

Virion Assembly ◽

N Protein ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions

AbstractThe multifunctional nucleocapsid (N) protein in SARS-CoV-2 binds the ~30 kb viral RNA genome to aid its packaging into the 80–90 nm membrane-enveloped virion. The N protein is composed of N-terminal RNA-binding and C-terminal dimerization domains that are flanked by three intrinsically disordered regions. Here we demonstrate that the N protein’s central disordered domain drives phase separation with RNA, and that phosphorylation of an adjacent serine/arginine rich region modulates the physical properties of the resulting condensates. In cells, N forms condensates that recruit the stress granule protein G3BP1, highlighting a potential role for N in G3BP1 sequestration and stress granule inhibition. The SARS-CoV-2 membrane (M) protein independently induces N protein phase separation, and three-component mixtures of N + M + RNA form condensates with mutually exclusive compartments containing N + M or N + RNA, including annular structures in which the M protein coats the outside of an N + RNA condensate. These findings support a model in which phase separation of the SARS-CoV-2 N protein contributes both to suppression of the G3BP1-dependent host immune response and to packaging genomic RNA during virion assembly.

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Antiviral Natural Products for Arbovirus Infections

Molecules ◽

10.3390/molecules25122796 ◽

2020 ◽

Vol 25 (12) ◽

pp. 2796 ◽

Cited By ~ 4

Author(s):

Vanessa Shi Li Goh ◽

Chee-Keng Mok ◽

Justin Jang Hann Chu

Keyword(s):

Natural Products ◽

Side Effects ◽

Plant Extracts ◽

Antiviral Drug ◽

Good Tolerability ◽

Antiviral Compounds ◽

Potential Source ◽

Herbal Plants ◽

Antiviral Activities ◽

Arboviral Diseases

Over the course of the last 50 years, the emergence of several arboviruses have resulted in countless outbreaks globally. With a high proportion of infections occurring in tropical and subtropical regions where arthropods tend to be abundant, Asia in particular is a region that is heavily affected by arboviral diseases caused by dengue, Japanese encephalitis, West Nile, Zika, and chikungunya viruses. Major gaps in protection against the most significant emerging arboviruses remains as there are currently no antivirals available, and vaccines are only available for some. A potential source of antiviral compounds could be discovered in natural products—such as vegetables, fruits, flowers, herbal plants, marine organisms and microorganisms—from which various compounds have been documented to exhibit antiviral activities and are expected to have good tolerability and minimal side effects. Polyphenols and plant extracts have been extensively studied for their antiviral properties against arboviruses and have demonstrated promising results. With an abundance of natural products to screen for new antiviral compounds, it is highly optimistic that natural products will continue to play an important role in contributing to antiviral drug development and in reducing the global infection burden of arboviruses.

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