Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents

Biomolecules, Год журнала: 2024, Номер 14(7), С. 797 - 797

Опубликована: Июль 4, 2024

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it significant target for developing antiviral drugs. inhibition Mpro has emerged as promising approach therapeutic agents to treat COVID-19. This review explores structure protein and analyzes progress made understanding protein–ligand interactions inhibitors. It focuses on binding kinetics, origin, chemical these provides in-depth analysis recent clinical trials involving covalent non-covalent inhibitors emerging dual targeting Mpro. By integrating findings from literature ongoing trials, this captures current state research into inhibitors, offering comprehensive challenges directions their future development anti-coronavirus agents. information new insights inspiration medicinal chemists, paving way more effective novel COVID-19 therapies.

Язык: Английский

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Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (M^pro)

ACS Omega, Год журнала: 2024, Номер 9(32), С. 34196 - 34219

Опубликована: Авг. 2, 2024

Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), by SARS-CoV-2 its variants, further highlighted urgent need for development effective therapeutic agents. Currently, highly conserved broad-spectrum nature main proteases (M

Язык: Английский

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Silaproline-bearing nirmatrelvir derivatives are potent inhibitors of the SARS-CoV-2 main protease highlighting the value of silicon-derivatives in structure-activity-relationship studies

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117603 - 117603

Опубликована: Апрель 1, 2025

Nirmatrelvir is a substrate-related inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (Mpro) that clinically used in combination with ritonavir to treat COVID-19. Derivatives nirmatrelvir, modified at substrate P2-equivalent position, have been developed fine-tune properties and are now clinical use. We report synthesis nirmatrelvir derivatives (R)-4,4-dimethyl-4-silaproline (silaproline) group position. Mass spectrometry (MS)-based assays demonstrate silaproline-bearing efficiently inhibit isolated recombinant Mpro, albeit reduced potency compared nirmatrelvir. Investigations SARS-CoV-2 infected VeroE6 cells reveal inhibitors CF3 P4-equivalent position viral progression, implying incorporating silicon atoms into Mpro can yield vivo active appropriate optimization. MS crystallographic studies show nucleophilic site cysteine residue (Cys145) reacts nitrile inhibitors. Substituting electrophilic for non-activated terminal alkyne shifts inhibition mode from reversible covalent irreversible inhibition. One two prochiral silaproline methyl groups occupies space S2 pocket unoccupied Mpro:nirmatrelvir complex structures, highlighting value sila-derivatives structure-activity-relationship (SAR) studies. The combined results highlight potential silicon-containing molecules and, by implication, other enzymes.

Язык: Английский

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Design, Synthesis, and Biological Evaluation of Peptidomimetic Tetrahydropyrrole Spirodihydroindolones as SARS-CoV-2 3CL Protease Inhibitors

ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер unknown

Опубликована: Апрель 14, 2025

Язык: Английский

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Mini review: SHEN26, a novel oral antiviral drug for COVID-19 treatment

Bioorganic & Medicinal Chemistry Letters, Год журнала: 2025, Номер unknown, С. 130243 - 130243

Опубликована: Апрель 1, 2025

Язык: Английский

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Pharmacokinetics and safety of GST-HG171, a novel 3CL protease inhibitor, in Chinese subjects with impaired and normal liver function

Antimicrobial Agents and Chemotherapy, Год журнала: 2024, Номер 68(8)

Опубликована: Июль 11, 2024

ABSTRACT GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C-like (3CL) protease inhibitor that was recently approved for treating mild to moderate coronavirus disease 2019 patients in China. Since cytochrome P450 (CYP) enzymes, primarily CYP3A, are the main metabolic enzymes of GST-HG171, hepatic impairment may affect its pharmacokinetic (PK) profile. Aiming guide clinical dosing with impairment, this study, using non-randomized, open-label, single-dose design, assessed impact on PK, safety, and tolerability GST-HG171. Patients along healthy subjects were enrolled ( n = 8 each), receiving single oral dose 150 mg concurrent administration 100 ritonavir sustain CYP3A inhibition before after (−12, 0, 12, 24 hours). Compared normal function, geometric least-squares mean ratios (90% confidence intervals) GST-HG171’s maximum plasma concentration C max ), area under concentration-time curve up last quantifiable time (AUC 0- t from 0 extrapolated infinity 0-∞ ) 1.14 (0.99, 1.31), 1.07 (0.88, 1.30), 1.29), respectively. For 0.87 (0.70, 1.07), 0.82 (0.61, 1.10), Hepatic did not significantly alter peak T elimination half-life 1/2 ). exhibited good safety study. Taken together, minimally impacted exposure, suggesting no need adjust dosage clinic. Clinical Trials Registered at ClinicalTrials.gov NCT06106113

Язык: Английский

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Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CLpro inhibitors against SARS-CoV-2

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 281, С. 117004 - 117004

Опубликована: Окт. 30, 2024

Язык: Английский

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Development of pyrimidone derivatives as nonpeptidic and noncovalent 3-chymotrypsin-like protease (3CLpro) inhibitors with anti-coronavirus activities

Bioorganic Chemistry, Год журнала: 2024, Номер 154, С. 107988 - 107988

Опубликована: Ноя. 22, 2024

Язык: Английский

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