Penicillin Derivatives Inhibit the SARS-CoV-2 Main Protease by Reaction with Its Nucleophilic Cysteine DOI Creative Commons
Tika R. Malla, Lennart Brewitz,

Dorian-Gabriel Muntean

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(11), P. 7682 - 7696

Published: May 12, 2022

The SARS-CoV-2 main protease (Mpro) is a medicinal chemistry target for COVID-19 treatment. Given the clinical efficacy of β-lactams as inhibitors bacterial nucleophilic enzymes, they are interest viral serine and cysteine proteases. We describe synthesis penicillin derivatives which potent Mpro investigate their mechanism inhibition using mass spectrometric crystallographic analyses. results suggest that have considerable potential via involving reaction with to form stable acyl-enzyme complex shown by analysis. highlight proteases employing catalysis related acylating agents.

Language: Английский

Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19 DOI Creative Commons
Yuto Unoh, Shota Uehara, Kenji Nakahara

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(9), P. 6499 - 6512

Published: March 30, 2022

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health safety. Despite the rapid global spread COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe discovery S-217622, first noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed biological an in-house compound library, optimization hit using a structure-based drug design strategy. exhibited activity vitro against current outbreaking variants showed favorable pharmacokinetic profiles vivo for once-daily dosing. Furthermore, dose-dependently inhibited intrapulmonary replication mice, indicating that this novel noncovalent could be potential agent treating COVID-19.

Language: Английский

Citations

446
Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses DOI Creative Commons
Andreas Luttens,

Hjalmar Gullberg,

Eldar Abdurakhmanov

et al.

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

Citations

188
The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19 DOI
Qing Hu, Yuan Xiong, Guanghao Zhu

et al.

MedComm, Journal Year: 2022, Volume and Issue: 3(3)

Published: July 14, 2022

The main proteases (M

Language: Английский

Citations

148
Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease DOI Creative Commons
Daniel W. Kneller, Hui Li, G.N. Phillips

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: April 27, 2022

Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (Mpro) is critical for virus replication thus considered attractive drug target. We performed design characterization three covalent hybrid inhibitors BBH-1, BBH-2 NBH-2 created by splicing components hepatitis C boceprevir narlaprevir, known SARS-CoV-1 inhibitors. A joint X-ray/neutron structure Mpro/BBH-1 complex demonstrates that a Cys145 thiolate reaction with inhibitor's keto-warhead creates negatively charged oxyanion. Protonation states ionizable residues in Mpro active site adapt inhibitor, which appears be intrinsic property Mpro. Structural comparisons PF-07321332 reveal unconventional F···O interactions may explain its more favorable enthalpy binding. exhibit comparable antiviral properties vitro relative PF-07321332, making them good candidates further improved antivirals.

Language: Английский

Citations

100
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors DOI Creative Commons
Melissa L. Boby, D. Fearon, Matteo P. Ferla

et al.

Science, Journal Year: 2023, Volume and Issue: 382(6671)

Published: Nov. 9, 2023

We report the results of COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. discovered noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, high-throughput structural biology chemistry. generated detailed map plasticity SARS-CoV-2 protease, extensive structure-activity relationships for multiple chemotypes, wealth biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay (>10,000 measurements), synthesized molecules (>2400 compounds) this were shared rapidly openly, creating rich, open, intellectual property–free knowledge base future anticoronavirus discovery.

Language: Английский

Citations

92
Antiviral Drug Discovery for the Treatment of COVID-19 Infections DOI Creative Commons
Teresa I. Ng, Ivan Correia, Jane Seagal

et al.

Viruses, Journal Year: 2022, Volume and Issue: 14(5), P. 961 - 961

Published: May 4, 2022

The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting vaccinated from infection, reducing severity of disease, and deterring transmission infection. However, vaccination faces many challenges, such as decline vaccine-induced immunity over time, decrease potency against some SARS-CoV-2 variants including Omicron variant, resulting breakthrough infections. challenges that facing highlight importance discovery antivirals serve another means tackle pandemic. To date, neutralizing antibodies block viral entry targeting spike protein make up largest class has received US FDA emergency use authorization (EUA) for treatment. In addition protein, other key targets direct-acting include enzymes are essential replication, RNA-dependent RNA polymerase proteases, judged approval remdesivir, EUA Paxlovid (nirmatrelvir + ritonavir) treating This review presents an overview current status future direction antiviral drug infections, covering important non-structural (nsp) 3 papain-like protease, nsp5 main nsp12/nsp7/nsp8 complex.

Language: Английский

Citations

80
Inhibition of the main protease of SARS-CoV-2 (Mpro) by repurposing/designing drug-like substances and utilizing nature’s toolbox of bioactive compounds DOI Creative Commons
Io Antonopoulou, Eleftheria Sapountzaki, Ulrika Rova

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2022, Volume and Issue: 20, P. 1306 - 1344

Published: Jan. 1, 2022

The emergence of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a long pandemic, with numerous cases and victims worldwide enormous consequences on social economic life. Although vaccinations have proceeded provide valuable shield against virus, approved drugs are limited it is crucial that further ways to combat infection developed, can also act potential mutations. main protease (Mpro) virus an appealing target for development inhibitors, due its importance viral life cycle high conservation among different coronaviruses. Several compounds shown inhibitory Mpro, both silico vitro, few them having entered clinical trials. These candidates include: known been repurposed, molecules specifically designed based natural substrate or structural moieties binding affinity active site, as well naturally derived compounds, either isolated plant extracts. aim this work collectively present results research regarding Mpro inhibitors date, focusing function founded by simulations explored vitro vivo assays. Creating extended portfolio promising may block replication inhibiting understanding involved structure-activity relationships, could basis effective solutions SARS-CoV-2 future related outbreaks.

Language: Английский

Citations

70
Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro DOI Creative Commons
Ningke Hou, Lei Shuai, Lijing Zhang

et al.

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(2), P. 217 - 227

Published: Jan. 25, 2023

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses thus a target coronavirus drug discovery. Nearly all inhibitors 3CLpro reported so far are covalent inhibitors. Here, we report development specific, noncovalent 3CLpro. most potent one, WU-04, effectively blocks replications in human cells with EC50 values 10-nM range. WU-04 also inhibits SARS-CoV MERS-CoV high potency, indicating that it pan-inhibitor showed anti-SARS-CoV-2 activity similar to PF-07321332 (Nirmatrelvir) K18-hACE2 mice when same dose was administered orally. Thus, promising candidate treatment.

Language: Английский

Citations

63
A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants DOI Creative Commons
Chong Huang, Huiping Shuai, Jingxin Qiao

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 16, 2023

Abstract Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten global public health. Small molecule antivirals are an effective treatment strategy to fight against virus. However, first-generation either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across globe, they face great pressure drug resistance. We herein present discovery characterization a new generation antiviral candidate (SY110), which is potent selective inhibitor main protease (M pro ). This compound displayed vitro activity not only predominant sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 MERS-CoV. In Omicron-infected K18-hACE2 mouse model, oral SY110 significantly lowered viral burdens lung alleviated virus-induced pathology. Importantly, possesses favorable PK properties high exposure bioavailability, outstanding safety profile. Furthermore, exhibited sensitivity several drug-resistance M mutations. Collectively, this investigation provides promising variants SARS-CoV-2.

Language: Английский

Citations

54
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

52