New Perspectives on Antimicrobial Agents: Molnupiravir and Nirmatrelvir/Ritonavir for Treatment of COVID-19 DOI
Robert L. Atmar, Natalie Finch

Antimicrobial Agents and Chemotherapy, Journal Year: 2022, Volume and Issue: 66(8)

Published: July 12, 2022

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged to cause pandemic disease in the past 2 years, leading significant worldwide morbidity and mortality. At beginning of pandemic, only nonspecific treatments were available, but recently two oral antivirals have received emergency use authorization from U.S. Food Drug Administration for treatment mild moderate coronavirus (COVID-19). Molnupiravir targets viral polymerase causes lethal mutations within virus during replication. Nirmatrelvir SARS-CoV-2's main protease, it is combined with ritonavir delay its metabolism allow nirmatrelvir inhibit proteolytic cleavage polyproteins replication, preventing efficient production. Both drugs

Language: Английский

Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern DOI Creative Commons
Laura Vangeel, Winston Chiu, Steven De Jonghe

et al.

Antiviral Research, Journal Year: 2022, Volume and Issue: 198, P. 105252 - 105252

Published: Jan. 24, 2022

We assessed the in vitro antiviral activity of remdesivir and its parent nucleoside GS-441524, molnupiravir EIDD-1931 viral protease inhibitor nirmatrelvir against ancestral SARS-CoV2 strain five variants concern including Omicron. VeroE6-GFP cells were pre-treated overnight with serial dilutions compounds before infection. The GFP signal was determined by high-content imaging on day 4 post-infection. All molecules have equipotent virus VOCs Alpha, Beta, Gamma, Delta These findings are line observation that target proteins these antivirals (respectively RNA dependent polymerase main Mpro) highly conserved.

Language: Английский

Citations

389
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
ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies DOI Creative Commons
Jun Siong Low, Josipa Jerak, M. Alejandra Tortorici

et al.

Science, Journal Year: 2022, Volume and Issue: 377(6607), P. 735 - 742

Published: July 12, 2022

The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind all human-infecting proteins from severe acute respiratory syndrome 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide acquire affinity breadth through somatic mutations. Despite targeting conserved motif, only some show neutralizing activity in vitro against alpha- betacoronaviruses, including animal coronaviruses WIV-1 PDF-2180. Two selected also neutralize Omicron BA.1 BA.2 authentic viruses reduce burden pathology vivo. Structural functional analyses showed peptide–specific bound with different modalities cryptic epitope hidden prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme (ACE2) or ACE2-mimicking mAbs.

Language: Английский

Citations

146
The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir DOI Creative Commons
Dirk Jochmans, Liu C,

Kim Donckers

et al.

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

Published: Jan. 10, 2023

The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for treatment of COVID-19. potential 3CLpro-inhibitors to select drug-resistant variants needs be established. Therefore, was passaged vitro presence increasing concentrations ALG-097161, probe compound designed context 3CLpro drug discovery program. We identified combination amino acid substitutions (L50F E166A L167F) that associated with >20× increase 50% effective concentration (EC50) values nirmatrelvir (PF-07321332), PF-00835231, ensitrelvir. While two single (E166A provide low-level resistance inhibitors biochemical assay, triple mutant results highest levels (6× 72×). All are significant loss enzymatic activity, suggesting reduction fitness. Structural biology analysis indicates different reduce number inhibitor/enzyme interactions while binding substrate maintained. These observations will important interpretation development clinical setting. IMPORTANCE Paxlovid first oral antiviral approved infection. Antiviral treatments often viruses. In order guide use novel antivirals, it essential understand risk characterize changes genes proteins. this work, we describe time pathway allows develop against vitro. characteristics may predictive situation. our work management COVID-19 next-generation inhibitors.

Language: Английский

Citations

132
Molecular characteristics, immune evasion, and impact of SARS-CoV-2 variants DOI Creative Commons
Cong Sun, Chu Xie,

Guo‐Long Bu

et al.

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

Published: June 28, 2022

Abstract The persistent COVID-19 pandemic since 2020 has brought an enormous public health burden to the global society and is accompanied by various evolution of virus genome. consistently emerging SARS-CoV-2 variants harboring critical mutations impact molecular characteristics viral proteins display heterogeneous behaviors in immune evasion, transmissibility, clinical manifestation during infection, which differ each strain endow them with distinguished features populational spread. Several variants, identified as Variants Concern (VOC) World Health Organization, challenged efforts on control due rapid worldwide spread enhanced evasion from current antibodies vaccines. Moreover, recent Omicron variant even exacerbated anxiety continuous pandemic. Its significant medical treatment disease highlights necessity combinatory investigation mutational pattern influence dynamics against immunity, would greatly facilitate drug vaccine development benefit policymaking. Hence this review, we summarized characteristics, impacts focused parallel comparison different profile, transmissibility tropism alteration, effectiveness, manifestations, order provide a comprehensive landscape for research.

Language: Английский

Citations

116
The omicron (B.1.1.529) SARS-CoV-2 variant of concern does not readily infect Syrian hamsters DOI Creative Commons
Rana Abdelnabi, Caroline S. Foo, Xin Zhang

et al.

Antiviral Research, Journal Year: 2022, Volume and Issue: 198, P. 105253 - 105253

Published: Jan. 21, 2022

The emergence of SARS-CoV-2 variants concern (VoCs) has exacerbated the COVID-19 pandemic. End November 2021, a new variant namely omicron (B.1.1.529) emerged. Since this is heavily mutated in spike protein, WHO classified as 5th (VoC). We previously demonstrated that ancestral strain and other VoCs replicate efficiently cause COVID19-like pathology Syrian hamsters. here wanted to explore infectivity comparison D614G hamster model. Strikingly, hamsters had been infected with variant, 3 log

Language: Английский

Citations

115
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

101
Accelerating antiviral drug discovery: lessons from COVID-19 DOI Open Access
Annette von Delft, Matthew D. Hall, Ann D. Kwong

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(7), P. 585 - 603

Published: May 12, 2023

Language: Английский

Citations

100
Oral Nirmatrelvir/Ritonavir Therapy for COVID-19: The Dawn in the Dark? DOI Creative Commons
Yuan‐Pin Hung, Jen‐Chieh Lee,

Chun-Wei Chiu

et al.

Antibiotics, Journal Year: 2022, Volume and Issue: 11(2), P. 220 - 220

Published: Feb. 9, 2022

Nirmatrelvir/ritonavir (Paxlovid™) is an effective and safe antiviral drug that inhibits the main protease (Mpro), 3CL protease, of SARS-CoV-2. A reduction in COVID-19-related hospitalization or death was observed patients treated with nirmatrelvir/ritonavir within five days symptom onset. Moreover, good oral availability enables usage nirmatrelvir/ritonavir, not only hospitalized patients, but also among outpatients. Nirmatrelvir (PF-07321332) has been demonstrated to stop spread COVID-19 animal models. Despite frequent mutations viral genomes SARS-CoV-2, nirmatrelvir shows effect against recent coronavirus mutants. promising nirmatrelvir, there are several unresolved concerns. First, final results large-scale clinical trials for early therapy mild cases yet published. Second, effectiveness upcoming variants coming years requires close monitoring. Considering preliminary EPIC-HR trial, conjunction vaccines non-pharmacological interventions, may represent dawn dark pandemic.

Language: Английский

Citations

89
S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters DOI Creative Commons
Michihito Sasaki, Koshiro Tabata, Mai Kishimoto

et al.

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 15(679)

Published: Nov. 3, 2022

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Oral medication demands not only high activity but also target specificity, favorable bioavailability, and metabolic stability. Although a large number compounds have been identified potential inhibitors SARS-CoV-2 infection in vitro, few proven be effective vivo. Here, we show that administration S-217622 (ensitrelvir), an inhibitor main protease (Mpro; known 3C-like protease), decreases viral load ameliorates severity SARS-CoV-2-infected hamsters. inhibited proliferation at low nanomolar submicromolar concentrations cells. demonstrated pharmacokinetic properties accelerated recovery from hamster recipients. Moreover, exerted against variants concern, including pathogenic Delta variant recently emerged Omicron BA.5 BA.2.75 variants. Overall, our study provides evidence S-217622, agent is under evaluation phase 3 clinical trial (clinical registration no. jRCT2031210350), has remarkable potency efficacy prospective therapeutic option COVID-19.

Language: Английский

Citations

79