Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease DOI

Yuya Hirose,

Naoya Shindo,

Makiko Mori

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(20), P. 13852 - 13865

Published: Oct. 13, 2022

The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome 2 (SARS-CoV-2). 3C-like protease (3CLpro) is a promising target for COVID-19 treatment. Here, we report new class covalent inhibitors 3CLpro that possess chlorofluoroacetamide (CFA) as cysteine-reactive warhead. Based on an aza-peptide scaffold, synthesized series CFA derivatives in enantiopure form and evaluated their biochemical efficiency. data revealed 8a (YH-6) with R configuration at unit strongly blocks SARS-CoV-2 replication infected cells, its potency comparable to nirmatrelvir. X-ray structural analysis showed YH-6 formed bond Cys145 catalytic center 3CLpro. strong activity favorable pharmacokinetic properties suggest potential lead compound treatment COVID-19.

Language: Английский

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease DOI
Haozhou Tan, Yanmei Hu, Prakash D. Jadhav

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(11), P. 7561 - 7580

Published: May 27, 2022

SARS-CoV-2 is the causative agent of COVID-19 pandemic. The approval vaccines and small-molecule antivirals vital in combating viral polymerase inhibitors remdesivir molnupiravir main protease inhibitor nirmatrelvir/ritonavir have been approved by U.S. FDA. However, emergence variants concern/interest calls for additional with novel mechanisms action. papain-like (PLpro) mediates cleavage polyprotein modulates host's innate immune response upon infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements structure-based design high-throughput screening PLpro since beginning Encouraging progress includes non-covalent favorable pharmacokinetic properties first-in-class covalent inhibitors. In addition, we offer our opinion on knowledge gaps that need to be filled advance clinic.

Language: Английский

Citations

119
Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives DOI Creative Commons
Gabriele La Monica, Alessia Bono, Antonino Lauria

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(19), P. 12500 - 12534

Published: Sept. 28, 2022

The viral main protease is one of the most attractive targets among all key enzymes involved in SARS-CoV-2 life cycle. Covalent inhibition cysteine145 MPRO with selective antiviral drugs will arrest replication process virus without affecting human catalytic pathways. In this Perspective, we analyzed silico, vitro, and vivo data representative examples covalent inhibitors reported literature to date. particular, studied molecules were classified into eight different categories according their reactive electrophilic warheads, highlighting differences between reversible/irreversible mechanism inhibition. Furthermore, analyses recurrent pharmacophoric moieties stereochemistry chiral carbons reported. noncovalent silico protocols, provided would be useful for scientific community discover new more efficient inhibitors.

Language: Английский

Citations

107
Evolutionary and Structural Insights about Potential SARS-CoV-2 Evasion of Nirmatrelvir DOI
Kai S. Yang,

Sunshine Z. Leeuwon,

Shiqing Xu

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(13), P. 8686 - 8698

Published: June 22, 2022

The U.S. FDA approval of PAXLOVID, a combination therapy nirmatrelvir and ritonavir has significantly boosted our morale in fighting the COVID-19 pandemic. Nirmatrelvir is an inhibitor main protease (MPro) SARS-CoV-2. Since many SARS-CoV-2 variants that resist vaccines antibodies have emerged, concern acquired viral resistance to naturally arises. Here, possible mutations MPro confer evasion are analyzed discussed from both evolutionary structural standpoints. analysis indicates those will likely reside whole aa45–51 helical region residues including M165, L167, P168, R188, Q189. Relevant also been observed existing samples. Implications this fight against future drug-resistant development broad-spectrum antivirals as well.

Language: Английский

Citations

96
Small molecules in the treatment of COVID-19 DOI Creative Commons
Sibei Lei, Xiaohua Chen, Jieping Wu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Language: Английский

Citations

85
An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron DOI Open Access
Baoxue Quan, Huiping Shuai, Anjie Xia

et al.

Nature Microbiology, Journal Year: 2022, Volume and Issue: 7(5), P. 716 - 725

Published: April 27, 2022

Language: Английский

Citations

84
The research progress of SARS-CoV-2 main protease inhibitors from 2020 to 2022 DOI Open Access

Xiaojing Pang,

Wei Xu, Yang Liu

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 257, P. 115491 - 115491

Published: May 22, 2023

Language: Английский

Citations

66
Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China DOI Open Access
Liyan Yang, Zhonglei Wang

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 257, P. 115503 - 115503

Published: May 18, 2023

Language: Английский

Citations

65
Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update DOI

Laura Hillebrand,

Xiaojun Julia Liang,

Ricardo A. M. Serafim

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7668 - 7758

Published: May 7, 2024

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.

Language: Английский

Citations

55
Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review DOI Creative Commons
Xin Li, Yongcheng Song

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 260, P. 115772 - 115772

Published: Aug. 28, 2023

Language: Английский

Citations

53
Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine DOI Creative Commons
Lennart Brewitz, Leo Dumjahn, Yilin Zhao

et al.

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

Citations

50