De Novo Discovery of a Noncovalent Cell-Penetrating Bicyclic Peptide Inhibitor Targeting SARS-CoV-2 Main Protease DOI

Yahong Tan,

Jinyue Yang, Min Wang

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(22), P. 20258 - 20274

Published: Nov. 18, 2024

Macrocyclic peptides have garnered significant attention as promising drug candidates. However, they typically face challenges in achieving and enhancing cell permeability for access to intracellular targets. In this study, we focused on the de novo screening of macrocyclic peptide inhibitors against main protease (Mpro) SARS-CoV-2 identified novel noncovalently bound that effectively inhibit proteolytic activity. High-resolution crystal structures further revealed molecular interactions between Mpro. Subsequently, a specific lacking was optimized transformed into low-toxicity, metabolically stable bicyclic with penetration capacity therapeutic potential SARS-CoV-2. The achieved using strategy involved introducing both structure bridging perfluorobiphenyl group. Our study not only provides lead inhibitor COVID-19 but also offers valuable insights through strategic modifications.

Language: Английский

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
Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19 DOI Creative Commons

Long Mao,

Namir Shaabani, Xiaoying Zhang

et al.

Med, Journal Year: 2024, Volume and Issue: 5(1), P. 42 - 61.e23

Published: Jan. 1, 2024

BackgroundOral antiviral drugs with improved potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks rebound, drug-drug interactions, emerging resistance.MethodsOlgotrelvir (STI-1558) is designed as a next-generation targeting SARS-CoV-2 main protease (Mpro), an essential enzyme replication, human cathepsin L (CTSL), key entry into host cells.FindingsOlgotrelvir highly bioavailable oral prodrug that converted plasma its active form, AC1115. The dual mechanism action olgotrelvir AC1115 was confirmed by activity inhibition assays co-crystal structures Mpro CTSL. displayed inhibiting replication all tested variants cell culture systems. Olgotrelvir also inhibited viral cells using Spike-mediated pseudotypes In K18-hACE2 transgenic mouse model SARS-CoV-2-mediated disease, significantly reduced virus load lungs, prevented body weight loss, cytokine release lung pathologies. demonstrated potent against nirmatrelvir-resistant E166 mutants. showed enhanced bioavailability animal models humans significant exposure without ritonavir. phase I studies (ClinicalTrials.gov: NCT05364840 NCT05523739), favorable profile activity.ConclusionsOlgotrelvir inhibitor CTSL high standalone candidate COVID-19.FundingFunded Sorrento Therapeutics.

Language: Английский

Citations

23
Molecular mechanism of ensitrelvir inhibiting SARS-CoV-2 main protease and its variants DOI Creative Commons
Meng-Meng Lin, Xudong Zeng, Yinkai Duan

et al.

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: July 5, 2023

Abstract SARS-CoV-2 poses an unprecedented threat to the world as causative agent of COVID-19 pandemic. Among a handful therapeutics developed for prevention and treatment infection, ensitrelvir is first noncovalent nonpeptide oral inhibitor targeting main protease (M pro ) SARS-CoV-2, which recently received emergency regulatory approval in Japan. Here we determined 1.8-Å structure M complex with ensitrelvir, revealed that targets substrate-binding pocket , specifically recognizing its S1, S2, S1' subsites. Further, our comprehensive biochemical structural data have demonstrated even though nirmatrelvir (an FDA-approved drug) belong different types inhibitors, both them remain be effective against s from all five variants concern, suggesting bona fide broad-spectrum target. The molecular mechanisms uncovered this study provide basis future design.

Language: Английский

Citations

38
Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives DOI Creative Commons
Andrea Citarella, Alessandro Dimasi, Davide Moi

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(9), P. 1339 - 1339

Published: Sept. 2, 2023

The main protease (Mpro) plays a pivotal role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is considered highly conserved viral target. Disruption catalytic activity Mpro produces detrimental effect on course infection, making this target one most attractive for treatment COVID-19. current success SARS-CoV-2 inhibitor Nirmatrelvir, first oral drug forms COVID-19, has further focused attention researchers important target, search new inhibitors thriving exciting field development antiviral drugs active against related coronaviruses.

Language: Английский

Citations

29
Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors DOI Creative Commons
Sven Falke, J. Lieske, Alexander Herrmann

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(9), P. 7048 - 7067

Published: April 17, 2024

Emerging RNA viruses, including SARS-CoV-2, continue to be a major threat. Cell entry of SARS-CoV-2 particles via the endosomal pathway involves cysteine cathepsins. Due ubiquitous expression, cathepsin L (CatL) is considered promising drug target in context different viral and lysosome-related diseases. We characterized anti-SARS-CoV-2 activity set carbonyl- succinyl epoxide-based inhibitors, which were previously identified as inhibitors cathepsins or related proteases. Calpain inhibitor XII, MG-101, CatL IV possess antiviral very low nanomolar EC50 range Vero E6 cells inhibit picomolar Ki range. show relevant off-target effect inhibition by coronavirus main protease α-ketoamide 13b. Crystal structures complex with 14 compounds at resolutions better than 2 Å present solid basis for structure-guided understanding optimization toward development.

Language: Английский

Citations

7
Research progress and perspectives of dual-target inhibitors DOI

Xiaojing Pang,

Wenyan Xu,

Jing Liang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117453 - 117453

Published: Feb. 26, 2025

Language: Английский

Citations

1
Recent Advances on SARS-CoV-2 Mpro Inhibitors: From Nirmatrelvir to Future Perspectives DOI Open Access
Andrea Citarella, Alessandro Dimasi, Davide Moi

et al.

Published: Aug. 2, 2023

The Main Protease (Mpro) plays a pivotal role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is considered highly conserved viral target. Disruption catalytic activity Mpro produces detrimental effect on course infection, making this target one most attractive for treatment COVID-19. current success SARS-CoV-2 inhibitor Nirmatrelvir, first oral drug forms COVID-19, has further focused attention researchers important target, search new inhibitors thriving exciting field development antiviral drugs active against related coronaviruses.

Language: Английский

Citations

14
Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group DOI
Pengxuan Ren, Hui Li, Tianqing Nie

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(17), P. 12266 - 12283

Published: Aug. 18, 2023

3CLpro is an attractive target for the treatment of COVID-19. Using scaffold hopping strategy, we identified a potent inhibitor (3a) that contains thiocyanate moiety as novel warhead can form covalent bond with Cys145 protein. Tandem mass spectrometry (MS/MS) and X-ray crystallography confirmed mechanism formation between 3a protein in its catalytic pocket. Moreover, several analogues compound were designed synthesized. Among them, 3h shows best inhibition IC50 0.322 μM kinact/Ki value 1669.34 M–1 s–1, it exhibits good selectivity against host proteases. Compound 3c inhibits SARS-CoV-2 Vero E6 cells (EC50 = 2.499 μM) low cytotoxicity (CC50 > 200 μM). These studies provide ideas insights to explore develop new inhibitors future.

Language: Английский

Citations

14
Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease DOI Creative Commons

Chau Ngo,

William Fried,

Saba R. Aliyari

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(17), P. 12237 - 12248

Published: Aug. 18, 2023

There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease M

Language: Английский

Citations

14
Discovery of PLpro and Mpro Inhibitors for SARS-CoV-2 DOI Creative Commons
Ana C. Puhl, André S. Godoy, G.D. Noske

et al.

ACS Omega, Journal Year: 2023, Volume and Issue: 8(25), P. 22603 - 22612

Published: June 14, 2023

There are very few small-molecule antivirals for SARS-CoV-2 that either currently approved (or emergency authorized) in the US or globally, including remdesivir, molnupiravir, and paxlovid. The increasing number of variants have appeared since outbreak began over three years ago raises need continual development updated vaccines orally available order to fully protect treat population. viral main protease (Mpro) papain-like (PLpro) key replication; therefore, they represent valuable targets antiviral therapy. We herein describe an vitro screen performed using 2560 compounds from Microsource Spectrum library against Mpro PLpro attempt identify additional hits could be repurposed SARS-CoV-2. subsequently identified 2 8 PLpro. One these was quaternary ammonium compound cetylpyridinium chloride with dual activity (IC50 = 2.72 ± 0.09 μM IC50 7.25 0.15 Mpro). A second inhibitor selective estrogen receptor modulator raloxifene 3.28 0.29 42.8 6.7 additionally tested several kinase inhibitors olmutinib 0.54 0.04 μM), bosutinib 4.23 0.28 crizotinib 3.81 dacominitinib 3.33 0.06 μM) as first time. In some cases, molecules also been by others this virus, we used Calu-3 cells infected results suggest drugs can promising proteases, cases validated their activity. identification known targeting may provide new repurposing opportunities starting points chemical optimization.

Language: Английский

Citations

12