Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
1.
Virol Sin ; 37(3): 418-426, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1967215

ABSTRACT

The global spread of enteroviruses (EVs) has become more frequent, severe and life-threatening. Intereron (IFN) I has been proved to control EVs by regulating IFN-stimulated genes (ISG) expression. 2'-5'-oligoadenylate synthetases 3 (OAS3) is an important ISG in the OAS/RNase L antiviral system. The relationship between OAS3 and EVs is still unclear. Here, we reveal that OAS3, superior to OAS1 and OAS2, significantly inhibited EV71 replication in vitro. However, EV71 utilized autologous 3C protease (3Cpro) to cleave intracellular OAS3 and enhance viral replication. Rupintrivir, a human rhinovirus 3C protease inhibitor, completely abolished the cleavage of EV71 3Cpro on OAS3. And the proteolytically deficient mutants H40G, E71A, and C147G of EV71 3Cpro also lost the ability of OAS3 cleavage. Mechanistically, the Q982-G983 motif in C-terminal of OAS3 was identified as a crucial 3Cpro cutting site. Further investigation indicated that OAS3 inhibited not only EV71 but also Coxsackievirus B3 (CVB3), Coxsackievirus A16 (CA16), Enterovirus D68 (EVD68), and Coxsackievirus A6 (CA6) subtypes. Notably, unlike other four subtypes, CA16 3Cpro could not cleave OAS3. Two key amino acids variation Ile36 and Val86 in CA16 3Cpro might result in weak and delayed virus replication of CA16 because of failure of OAS and 3AB cleavage. Our works elucidate the broad anti-EVs function of OAS3, and illuminate a novel mechanism by which EV71 use 3Cpro to escape the antiviral effect of OAS3. These findings can be an important entry point for developing novel therapeutic strategies for multiple EVs infection.


Subject(s)
Enterovirus A, Human , Enterovirus Infections , Enterovirus , 2',5'-Oligoadenylate Synthetase/genetics , 2',5'-Oligoadenylate Synthetase/metabolism , 2',5'-Oligoadenylate Synthetase/pharmacology , 3C Viral Proteases , Adenine Nucleotides , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Enterovirus/metabolism , Enterovirus A, Human/genetics , Humans , Ligases/pharmacology , Oligoribonucleotides , Peptide Hydrolases/pharmacology , Virus Replication
2.
Curr Pharm Biotechnol ; 23(7): 959-969, 2022.
Article in English | MEDLINE | ID: covidwho-1259293

ABSTRACT

BACKGROUND: There has been tremendous pressure on healthcare facilities globally due to the recent emergence of novel coronavirus infection known as COVID-19 and its rapid spread across the continents. The lack of effective therapeutics for the management of the pandemic calls for the discovery of new drugs and vaccines. OBJECTIVE: In the present study, a chemical library was screened for molecules against three coronavirus 3CL-like protease enzymes (SARS-CoV-2 3CLpro, SARS-CoV 3CLpro and MERS-CoV 3CLpro), which are a key player in the viral replication cycle. METHODS: Extensive computational methods such as virtual screening and molecular docking were employed in this study. RESULTS: Two lead molecules, ZINC08825480 (4-bromo-N'-{(E)-[1-phenyl-3-(pyridin-3-yl)-1H-pyrazol- 4-yl]methylidene}benzene-1-sulfonohydrazide) and ZINC72009942 (N-[[2-[[(3S)-3-methyl-1-piperidyl] methyl]phenyl]methyl]-6-oxo-1-(p-tolyl)-4,5-dihydro-1,2,4-triazine-3-carboxamide), were identified with better affinity with the three target enzymes as compared to the approved antiviral drugs. Both the lead molecules possessed favorable drug-like properties, fit well into the active site pocket close to His- Cys dyad and showed a good number of hydrogen bonds with the backbone as well as side chains of key amino acid residues. CONCLUSION: Thus, the present study offers two novel chemical entities against coronavirus infections which can be validated through various biological assays.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Peptide Hydrolases/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , SARS-CoV-2
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.
Cell Physiol Biochem ; 54(4): 767-790, 2020 Aug 25.
Article in English | MEDLINE | ID: covidwho-729851

ABSTRACT

The pandemic of the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 at the end of 2019 marked the third outbreak of a highly pathogenic coronavirus affecting the human population in the past twenty years. Cross-species zoonotic transmission of SARS-CoV-2 has caused severe pathogenicity and led to more than 655,000 fatalities worldwide until July 28, 2020. Outbursts of this virus underlined the importance of controlling infectious pathogens across international frontiers. Unfortunately, there is currently no clinically approved antiviral drug or vaccine against SARS-CoV-2, although several broad-spectrum antiviral drugs targeting multiple RNA viruses have shown a positive response and improved recovery in patients. In this review, we compile our current knowledge of the emergence, transmission, and pathogenesis of SARS-CoV-2 and explore several features of SARS-CoV-2. We emphasize the current therapeutic approaches used to treat infected patients. We also highlight the results of in vitro and in vivo data from several studies, which have broadened our knowledge of potential drug candidates for the successful treatment of patients infected with and discuss possible virus and host-based treatment options against SARS-CoV-2.


Subject(s)
Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/genetics , Betacoronavirus/physiology , COVID-19 , COVID-19 Vaccines , Coronaviridae/pathogenicity , Coronaviridae Infections/epidemiology , Coronaviridae Infections/virology , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Coronavirus Infections/transmission , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Cytokines/antagonists & inhibitors , Drug Delivery Systems , Endocytosis/drug effects , Forecasting , Genome, Viral , Global Health , Humans , Immunity, Herd , Immunization, Passive , Pandemics/prevention & control , Peptide Hydrolases/pharmacology , Peptide Hydrolases/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , RNA, Viral/genetics , Receptors, Coronavirus , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Viral Vaccines , Virus Internalization/drug effects , Virus Replication/drug effects , Zoonoses
SELECTION OF CITATIONS
SEARCH DETAIL