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1.
Expert Rev Vaccines ; 21(10): 1363-1376, 2022 10.
Article in English | MEDLINE | ID: covidwho-1972921

ABSTRACT

INTRODUCTION: Vaccination continues to be the most effective method for controlling COVID-19 infectious diseases. Nonetheless, SARS-CoV-2 variants continue to evolve and emerge, resulting in significant public concerns worldwide, even after more than 2 years since the COVID-19 pandemic. It is important to better understand how different COVID-19 vaccine platforms work, why SARS-CoV-2 variants continue to emerge, and what options for improving COVID-19 vaccines can be considered to fight against SARS-CoV-2 variants and future pandemics. AREA COVERED: Here, we reviewed the innate immune sensors in the recognition of SARS-CoV-2 virus, innate and adaptive immunity including neutralizing antibodies by different COVID-19 vaccines. Efficacy comparison of the several COVID-19 vaccine platforms approved for use in humans, concerns about SARS-CoV-2 variants and breakthrough infections, and the options for developing future COIVD-19 vaccines were also covered. EXPERT OPINION: Owing to the continuous emergence of novel pathogens and the reemergence of variants, safer and more effective new vaccines are needed. This review also aims to provide the knowledge basis for the development of next-generation COVID-19 and pan-coronavirus vaccines to provide cross-protection against new SARS-CoV-2 variants and future coronavirus pandemics.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Pandemics/prevention & control , SARS-CoV-2
2.
Brief Bioinform ; 22(2): 1361-1377, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1352114

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a dreaded pandemic in lack of specific therapeutic agent. SARS-CoV-2 Mpro, an essential factor in viral pathogenesis, is recognized as a prospective therapeutic target in drug discovery against SARS-CoV-2. To tackle this pandemic, Food and Drug Administration-approved drugs are being screened against SARS-CoV-2 Mpro via in silico and in vitro methods to detect the best conceivable drug candidates. However, identification of natural compounds with anti-SARS-CoV-2 Mpro potential have been recommended as rapid and effective alternative for anti-SARS-CoV-2 therapeutic development. Thereof, a total of 653 natural compounds were identified against SARS-CoV-2 Mpro from NP-lib database at MTi-OpenScreen webserver using virtual screening approach. Subsequently, top four potential compounds, i.e. 2,3-Dihydroamentoflavone (ZINC000043552589), Podocarpusflavon-B (ZINC000003594862), Rutin (ZINC000003947429) and Quercimeritrin 6"-O-L-arabinopyranoside (ZINC000070691536), and co-crystallized N3 inhibitor as reference ligand were considered for stringent molecular docking after geometry optimization by DFT method. Each compound exhibited substantial docking energy >-12 kcal/mol and molecular contacts with essential residues, including catalytic dyad (His41 and Cys145) and substrate binding residues, in the active pocket of SARS-CoV-2 Mpro against N3 inhibitor. The screened compounds were further scrutinized via absorption, distribution, metabolism, and excretion - toxicity (ADMET), quantum chemical calculations, combinatorial molecular simulations and hybrid QM/MM approaches. Convincingly, collected results support the potent compounds for druglikeness and strong binding affinity with the catalytic pocket of SARS-CoV-2 Mpro. Hence, selected compounds are advocated as potential inhibitors of SARS-CoV-2 Mpro and can be utilized in drug development against SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus M Proteins/drug effects , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Humans , Molecular Dynamics Simulation , Quantum Theory
3.
Life Sci ; 257: 118080, 2020 Sep 15.
Article in English | MEDLINE | ID: covidwho-1152544

ABSTRACT

The COVID-19 pandemic raised by SARS-CoV-2 is a public health emergency. However, lack of antiviral drugs and vaccine against human coronaviruses demands a concerted approach to challenge the SARS-CoV-2 infection. Under limited resource and urgency, combinatorial computational approaches to identify the potential inhibitor from known drugs could be applied against risen COVID-19 pandemic. Thereof, this study attempted to purpose the potent inhibitors from the approved drug pool against SARS-CoV-2 main protease (Mpro). To circumvent the issue of lead compound from available drugs as antivirals, antibiotics with broad spectrum of viral activity, i.e. doxycycline, tetracycline, demeclocycline, and minocycline were chosen for molecular simulation analysis against native ligand N3 inhibitor in SARS-CoV-2 Mpro crystal structure. Molecular docking simulation predicted the docking score >-7 kcal/mol with significant intermolecular interaction at the catalytic dyad (His41 and Cys145) and other essential substrate binding residues of SARS-CoV-2 Mpro. The best ligand conformations were further studied for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamics simulation, established the significant stability and interactions of selected antibiotics by comparison to N3 inhibitor. Based on combinatorial molecular simulation analysis, doxycycline and minocycline were selected as potent inhibitor against SARS-CoV-2 Mpro which can used in combinational therapy against SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/drug effects , Betacoronavirus/metabolism , Tetracyclines/pharmacology , Anti-Bacterial Agents , Antiviral Agents/pharmacology , Binding Sites/physiology , COVID-19 , Computational Biology/methods , Coronavirus Infections/drug therapy , Databases, Genetic , Humans , Ligands , Molecular Docking Simulation/methods , Molecular Dynamics Simulation , Pandemics , Peptide Hydrolases/drug effects , Peptide Hydrolases/pharmacology , Pneumonia, Viral/drug therapy , Protease Inhibitors , Protein Binding/drug effects , SARS-CoV-2 , Viral Nonstructural Proteins/antagonists & inhibitors
4.
Viruses ; 13(2)2021 02 15.
Article in English | MEDLINE | ID: covidwho-1122257

ABSTRACT

Coronavirus disease-19 (COVID-19) pandemic, caused by the novel SARS-CoV-2 virus, continues to be a global threat. The number of cases and deaths will remain escalating due to the lack of effective therapeutic agents. Several studies have established the importance of the viral main protease (Mpro) in the replication of SARS-CoV-2 which makes it an attractive target for antiviral drug development, including pharmaceutical repurposing and other medicinal chemistry approaches. Identification of natural products with considerable inhibitory potential against SARS-CoV-2 could be beneficial as a rapid and potent alternative with drug-likeness by comparison to de novo antiviral drug discovery approaches. Thereof, we carried out the structure-based screening of natural products from Echinacea-angustifolia, commonly used to prevent cold and other microbial respiratory infections, targeting SARS-CoV-2 Mpro. Four natural products namely, Echinacoside, Quercetagetin 7-glucoside, Levan N, Inulin from chicory, and 1,3-Dicaffeoylquinic acid, revealed significant docking energy (>-10 kcal/mol) in the SARS-CoV-2 Mpro catalytic pocket via substantial intermolecular contacts formation against co-crystallized ligand (<-4 kcal/mol). Furthermore, the docked poses of SARS-CoV-2 Mpro with selected natural products showed conformational stability through molecular dynamics. Exploring the end-point net binding energy exhibited substantial contribution of Coulomb and van der Waals interactions to the stability of respective docked conformations. These results advocated the natural products from Echinacea angustifolia for further experimental studies with an elevated probability to discover the potent SARS-CoV-2 Mpro antagonist with higher affinity and drug-likeness.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Echinacea/chemistry , Protease Inhibitors/chemistry , Binding Sites , Drug Discovery , Flavones/chemistry , Fructans/chemistry , Glycosides/chemistry , Inulin/chemistry , Molecular Docking Simulation , Phytochemicals/chemistry , Protein Binding , Quinic Acid/analogs & derivatives , Quinic Acid/chemistry
5.
Front Mol Biosci ; 7: 627842, 2020.
Article in English | MEDLINE | ID: covidwho-1058430

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as coronavirus disease 2019 (COVID-19) pandemic, has killed more than a million people worldwide, and researchers are constantly working to develop therapeutics in the treatment and prevention of this new viral infection. To infect and induced pathogenesis as observed in other viral infections, we postulated that SARS-CoV-2 may also require an escalation in the anabolic metabolism, such as glucose and glutamine, to support its energy and biosynthetic requirements during the infection cycle. Recently, the requirement of altered glucose metabolism in SARS-CoV-2 pathogenesis was demonstrated, but the role of dysregulated glutamine metabolism is not yet mentioned for its infection. In this perspective, we have attempted to provide a summary of possible biochemical events on putative metabolic reprograming of glutamine in host cells upon SARS-CoV-2 infection by comparison to other viral infections/cancer metabolism and available clinical data or research on SARS-CoV-2 pathogenesis. This systematic hypothesis concluded the vital role of glutaminase-1 (GLS1), phosphoserine aminotransferase (PSAT1), hypoxia-inducible factor-1 alpha (HIF-1α), mammalian target of rapamycin complex 1 (mTORC1), glutamine-fructose amidotransferase 1/2 (GFAT1/2), and transcription factor Myc as key cellular factors to mediate and promote the glutamine metabolic reprogramming in SARS-CoV-2 infected cells. In absence of concrete data available for SARS-CoV-2 induced metabolic reprogramming of glutamine, this study efforts to connect the gaps with available clinical shreds of evidence in SARS-CoV-2 infection with altered glutamine metabolism and hopefully could be beneficial in the designing of strategic methods for therapeutic development with elucidation using in vitro or in vivo approaches.

6.
J Biomol Struct Dyn ; 40(6): 2769-2784, 2022 04.
Article in English | MEDLINE | ID: covidwho-929708

ABSTRACT

Recent outbreak of COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has raised serious global concern for public health. The viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication and essential for viral life cycle, has been established as an essential drug discovery target for SARS-CoV-2. Herein, we employed computationally screening of Druglib database containing FDA approved drugs against active pocket of SARS-CoV-2 Mpro using MTiopen screen web server, yields a total of 1051 FDA approved drugs with docking energy >-7 kcal/mol. The top 10 screened potential compounds against SARS-CoV-2 Mpro were then studied by re-docking, binding affinity, intermolecular interaction, and complex stability via 100 ns all atoms molecular dynamics (MD) simulation followed by post-simulation analysis, including end point binding free energy, essential dynamics, and residual correlation analysis against native crystal structure ligand N3 inhibitor. Based on comparative molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 Mpro revealed R428 (-10.5 kcal/mol), Teniposide (-9.8 kcal/mol), VS-5584 (-9.4 kcal/mol), and Setileuton (-8.5 kcal/mol) with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using in vitro enzyme inhibition and in vivo studies against SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Protease Inhibitors/pharmacology
7.
Infect Genet Evol ; 85: 104502, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-712141

ABSTRACT

Human Coronaviruses (HCoV), periodically emerging across the world, are potential threat to humans such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) - diseases termed as COVID-19. Current SARS-CoV-2 outbreak have fueled ongoing efforts to exploit various viral target proteins for therapy, but strategies aimed at blocking the viral proteins as in drug and vaccine development have largely failed. In fact, evidence has now shown that coronaviruses undergoes rapid recombination to generate new strains of altered virulence; additionally, escaped the host antiviral defense system and target humoral immune system which further results in severe deterioration of the body such as by cytokine storm. This demands the understanding of phenotypic and genotypic classification, and pathogenesis of SARS-CoV-2 for the production of potential therapy. In lack of clear clinical evidences for the pathogenesis of COVID-19, comparative analysis of previous pandemic HCoVs associated immunological responses can provide insights into COVID-19 pathogenesis. In this review, we summarize the possible origin and transmission mode of CoVs and the current understanding on the viral genome integrity of known pandemic virus against SARS-CoV-2. We also consider the host immune response and viral evasion based on available clinical evidences which would be helpful to remodel COVID-19 pathogenesis; and hence, development of therapeutics against broad spectrum of coronaviruses.


Subject(s)
Coronavirus Infections/transmission , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Animals , Genome, Viral , Humans , Pandemics , Phylogeny , SARS Virus/chemistry , SARS Virus/classification , SARS Virus/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/classification , SARS-CoV-2/genetics , Virulence
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