Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(8), P. 1658 - 1669

Published: July 24, 2023

The SARS-CoV-2 main protease (Mpro) is the drug target of Pfizer's oral nirmatrelvir. emergence variants with mutations in Mpro raised alarm potential resistance. To identify clinically relevant drug-resistant mutants, we systematically characterized 102 naturally occurring mutants located at 12 residues nirmatrelvir-binding site, among which 22 5 residues, including S144M/F/A/G/Y, M165T, E166 V/G/A, H172Q/F, and Q192T/S/L/A/I/P/H/V/W/C/F, showed comparable enzymatic activity to wild-type (kcat/Km < 10-fold change) while being resistant nirmatrelvir (Ki > increase). X-ray crystal structures were determined for six representative and/or without GC-376/nirmatrelvir. Using recombinant viruses generated from reverse genetics, confirmed resistance antiviral assay that reduced had attenuated viral replication. Overall, our study identified several hotspots warrant close monitoring possible clinical evidence resistance, some have already emerged independent passage assays conducted by others.

Language: Английский

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SARS-CoV-2 3CL ^pro mutations selected in a VSV-based system confer resistance to nirmatrelvir, ensitrelvir, and GC376

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 15(678)

Published: Oct. 4, 2022

Protease inhibitors are among the most powerful antiviral drugs. Nirmatrelvir is first protease inhibitor specifically developed against SARS-CoV-2 3CLpro that has been licensed for clinical use. To identify mutations confer resistance to this inhibitor, we engineered a chimeric vesicular stomatitis virus (VSV) expressed polyprotein composed of VSV glycoprotein (G), 3CLpro, and polymerase (L). Viral replication was thus dependent on autocatalytic processing precursor protein by release functional viral proteins G L, effectively inhibited nirmatrelvir. Using system, applied nirmatrelvir select mutations. Resistance confirmed retesting selected in additional VSV-based systems, an independently cellular biochemical assay, recombinant system. We demonstrate some mutants cross-resistant ensitrelvir GC376, whereas others less resistant these compounds. Furthermore, found already existed sequences have deposited NCBI GISAID databases, indicating were present circulating strains.

Language: Английский

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Accelerating antiviral drug discovery: lessons from COVID-19

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

Published: May 12, 2023

Language: Английский

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Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy?

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 162, P. 114367 - 114367

Published: Feb. 6, 2023

Despite the need for novel, effective therapeutics COVID-19 pandemic, no curative regimen is yet available, therefore patients are forced to rely on supportive and nonspecific therapies. Some SARS-CoV-2 proteins, like 3 C-like protease (3CLpro) or major (Mpro), have been identified as promising targets antiviral drugs. The Mpro has a role in protein processing well pathogenesis of virus, could be useful therapeutic target. drug nirmatrelvir can keep from replicating through inhibiting Mpro. Nirmatrelvir was combined with another HIV inhibitor, ritonavir, create Paxlovid (Nirmatrelvir/Ritonavir). metabolizing enzyme cytochrome P450 A inhibited by ritonavir lengthen half-life nirmatrelvir, so rintonavir acts pharmacological enhancer. exhibits potent activity against current coronavirus variants, despite significant alterations viral genome. Nevertheless, there still several unanswered questions. This review summarizes literature efficacy treating infection, also their safety possible side effects.

Language: Английский

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Small molecules in the treatment of COVID-19

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

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Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance

EBioMedicine, Journal Year: 2023, Volume and Issue: 91, P. 104559 - 104559

Published: April 14, 2023

Nirmatrelvir-ritonavir (Paxlovid) and ensitrelvir are 3-chymotrypsin-like cysteine protease (3CLpro) inhibitors which have been approved for the treatment of COVID-19 in 2021 2022, respectively. Previous studies identified 3CLpro mutations that associated with reduced susceptibility to these antivirals. The aim current study was estimate global prevalence inhibitor-resistant SARS-CoV-2 strains.We compiled a list nirmatrelvir or resistance based on either viral replication activity assays, determined their among 13.4 million sequences deposited GISAID as December 14, about 1 year after approval nirmatrelvir-ritonavir. We analyzed different time periods, lineages geographical locations.Overall, 0.5% (67,095/13,446,588) contained at least one mutation shown affect inhibitory activity. did not observe any increasing trend widespread clinical use G15S (2070 per million) T21I (1386 were most prevalent mutations, dominant some lineages. E166V S144E, previously by > 100-folds, found <1 sequences.Our data suggest inhibitor is currently rare. However, continuous genotypic phenotypic surveillance would be crucial early detection resistant mutants.Richard Carol Yu, May Tam Mak Mei Yin, Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, Emergency Key Program Guangzhou Laboratory (See acknowledgements full list).

Language: Английский

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Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: June 28, 2022

ABSTRACT The SARS-CoV-2 main protease (M pro ) is the drug target of Pfizer’s oral Paxlovid. emergence variants with mutations in M raised alarm potential resistance. In this study, we identified 100 naturally occurring located at nirmatrelvir binding site, among which 20 mutants, including S144M/F/A/G/Y, M165T, E166G, H172Q/F, and Q192T/S/L/A/I/P/H/V/W/C/F, showed comparable enzymatic activity to wild-type (k cat /K m <10-fold change) resistance (K i >10-fold increase). X-ray crystal structures were determined for seven representative mutants and/or without GC-376/nirmatrelvir. Viral growth assay that reduced led attenuated viral replication. Overall, our study several resistant hot spots warrant close monitoring possible clinical evidence Paxlovid One Sentence Summary viruses have been from isolates.

Language: Английский

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Therapeutics for COVID-19

Nature Microbiology, Journal Year: 2023, Volume and Issue: 8(5), P. 771 - 786

Published: May 4, 2023

Vaccines and monoclonal antibody treatments to prevent severe coronavirus disease 2019 (COVID-19) illness were available within a year of the pandemic being declared but there remained an urgent need for therapeutics treat patients who not vaccinated, immunocompromised or whose vaccine immunity had waned. Initial results investigational therapies mixed. AT-527, repurposed nucleoside inhibitor hepatitis C virus, enabled viral load reduction in hospitalized cohort did reduce outpatients. The molnupiravir prevented death failed hospitalization. Nirmatrelvir, main protease (Mpro), co-dosed with pharmacokinetic booster ritonavir, reduced hospitalization death. Nirmatrelvir–ritonavir received Emergency Use Authorization United States at end 2021. Immunomodulatory drugs such as baricitinib, tocilizumab corticosteroid, which target host-driven COVID-19 symptoms, are also use. We highlight development challenges that remain anticoronavirals. Therapeutics their during reviewed, including future prospects

Language: Английский

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A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants

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

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Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2

Med, Journal Year: 2023, Volume and Issue: 4(11), P. 813 - 824.e4

Published: Sept. 7, 2023

Antiviral and antibody therapies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being recommended high-risk patients, but the potential development of multidrug-resistant mutations in immunocompromised patients is unclear.To investigate treatment course cases prolonged viral shedding an patient with SARS-CoV-2 infection, we conducted longitudinal measurements laboratory tests, chest computed tomography (CT) image evaluations, titers, antigen levels nasopharyngeal swabs. Furthermore, performed whole-genome sequencing digital PCR analysis to examine mechanisms drug resistance.We present a case 65-year-old man history malignant lymphoma who was treated multiple antiviral therapies, including sotrovimab, remdesivir, paxlovid (nirmatrelvir/ritonavir), molnupiravir. Initially, decreased after treatments. However, virus rebounded, showed no virologic response. The genome revealed single Omicron subvariant (BA.1.1), which evolved within host during disease progression. viruses had acquired resistance nirmatrelvir (3 chymotrypsin-like protease [3CLpro] E166 A/V), sotrovimab (spike P337L E340K), remdesivir (RNA-dependent RNA polymerase [RdRp] V166L).Our results indicate that survival fitness persist infected subpopulation selection pressure.This study supported by JSPS KAKENHI Early-Career Scientists 18K16292 (Y.H.), Grant-in-Aid Scientific Research (B) 20H03668 23H02955 YASUDA Medical Foundation Uehara Memorial Takeda Science Kato Bioscience (Y.H.).

Language: Английский

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