Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis

Nature Structural & Molecular Biology, Journal Year: 2021, Volume and Issue: 28(9), P. 740 - 746

Published: Aug. 11, 2021

Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. increases frequency viral RNA mutations and impairs SARS-CoV-2 replication animal models humans. Here, we establish molecular mechanisms underlying molnupiravir-induced mutagenesis by RNA-dependent polymerase (RdRp). Biochemical assays show that RdRp uses active form molnupiravir, β-D-N

Language: Английский

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SARS-CoV-2 M ^pro inhibitors with antiviral activity in a transgenic mouse model

Science, Journal Year: 2021, Volume and Issue: 371(6536), P. 1374 - 1378

Published: Feb. 18, 2021

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both which are approved antivirals. All compounds inhibited activity vitro, with 50% inhibitory concentration values ranging 7.6 748.5 nM. cocrystal structure complex MI-23, one the most potent compounds, revealed its interaction mode. Two (MI-09 MI-30) showed excellent antiviral cell-based assays. In transgenic mouse model infection, oral intraperitoneal treatment MI-09 MI-30 significantly reduced lung loads lesions. Both also displayed good pharmacokinetic properties safety rats.

Language: Английский

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Molnupiravir in COVID-19: A systematic review of literature

Diabetes & Metabolic Syndrome Clinical Research & Reviews, Journal Year: 2021, Volume and Issue: 15(6), P. 102329 - 102329

Published: Oct. 30, 2021

Language: Английский

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Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(7), P. 2905 - 2920

Published: Feb. 10, 2022

Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies find main protease ultralarge chemical libraries. First, structure-based docking was used screen a diverse library 235 million compounds against active site. One hundred top-ranked were tested binding enzymatic assays. Second, fragment discovered by crystallographic optimized guided elaborated molecules experimental testing 93 compounds. Three identified first screen, five selected elaborations showed inhibitory effects. Crystal structures target-inhibitor complexes confirmed predictions hit-to-lead optimization, resulting noncovalent inhibitor with nanomolar affinity, promising vitro pharmacokinetic profile, broad-spectrum antiviral effect infected cells.

Language: Английский

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Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen

ACS Pharmacology & Translational Science, Journal Year: 2021, Volume and Issue: 4(3), P. 1096 - 1110

Published: March 11, 2021

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, main protease (3CL-Pro), also termed M-Pro, attractive drug target as it plays a central role in viral replication by processing polyproteins pp1a pp1ab at multiple distinct cleavage sites. We here report results program involving 8.7 K compounds containing marketed drugs, clinical preclinical candidates, small molecules regarded safe humans. confirmed previously reported inhibitors 3CL-Pro have identified 62 additional with IC50 values below 1 μM profiled their selectivity toward chymotrypsin from Middle East respiratory syndrome virus. A subset eight showed anticytopathic effect Vero-E6 cell line, thioguanosine MG-132 were analyzed predicted binding characteristics to 3CL-Pro. The X-ray crystal structure complex myricetin SARS-Cov-2 was solved resolution 1.77 Å, showing that covalently bound catalytic Cys145 therefore inhibiting its enzymatic activity.

Language: Английский

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The P132H mutation in the main protease of Omicron SARS-CoV-2 decreases thermal stability without compromising catalysis or small-molecule drug inhibition

Cell Research, Journal Year: 2022, Volume and Issue: 32(5), P. 498 - 500

Published: March 15, 2022

Language: Английский

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Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CL^pro)

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 65(4), P. 2880 - 2904

Published: Aug. 4, 2021

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including original were obtained proved instrumental guiding chemistry toward 41 (CCF0058981). The disclosed inhibitors utilize noncovalent mode action noncanonical binding not observed by peptidic inhibitors. In vitro DMPK profiling highlights key areas where further series is required to obtain useful vivo probes. Antiviral activity established using SARS-CoV-2-infected Vero E6 cell viability assay plaque formation assay. Compound demonstrates nanomolar these respective assays, comparable potency remdesivir. These findings have implications for antiviral development combat current future SARS-like zoonotic outbreaks.

Language: Английский

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Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 13, 2023

The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report development an orally bioavailable SARS-CoV-2 3C-like protease (3CL

Language: Английский

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Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(4), P. 2663 - 2680

Published: Feb. 9, 2023

Nirmatrelvir (PF-07321332) is a nitrile-bearing small-molecule inhibitor that, in combination with ritonavir, used to treat infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). interrupts the viral life cycle inhibiting SARS-CoV-2 main protease (Mpro), which essential for processing polyproteins into functional nonstructural proteins. We report studies reveal that derivatives of nirmatrelvir and other Mpro inhibitors nonactivated terminal alkyne group positioned similarly electrophilic nitrile can efficiently inhibit isolated replication cells. Mass spectrometric crystallographic evidence shows apparent irreversible covalent reactions active site cysteine (Cys145), while analogous nitriles react reversibly. The results highlight potential inhibition nucleophilic proteases alkynes, which, contrast nitriles, be functionalized at their position optimize selectivity, as well pharmacodynamic pharmacokinetic properties.

Language: Английский

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Identifying Inhibitor-SARS-CoV2-3CLpro Binding Mechanism Through Molecular Docking, GaMD Simulations, Correlation Network Analysis and MM-GBSA Calculations

Molecules, Journal Year: 2025, Volume and Issue: 30(4), P. 805 - 805

Published: Feb. 10, 2025

The main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as 3CLpro, is crucial in virus's life cycle and plays a pivotal role COVID-19. Understanding how small molecules inhibit 3CLpro's activity vital for developing anti-COVID-19 therapeutics. To this end, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to enhance sampling 3CLpro conformations conducted correlation network analysis (CNA) explore interactions between different structural domains. Our findings indicate that CNA-identified node domain II acts conduit, transferring conformational changes from catalytic regions domains I II, triggered by binding inhibitors (7YY, 7XB, Y6G), III, thereby modulating activity. Normal mode (NMA) principal component (PCA) revealed inhibitor affects flexibility collective movements sites influencing function. free energies, predicted both MM-GBSA QM/MM-GBSA methods, showed high with experimental data, validating reliability our analyses. Furthermore, residues L27, H41, C44, S46, M49, N142, G143, S144, C145, H163, H164, M165, E166, identified through residue-based energy decomposition, present promising targets design drugs could facilitate development clinically effective inhibitors.

Language: Английский

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