Nirmatrelvir Resistance—de Novo E166V/L50V Mutations in an Immunocompromised Patient Treated With Prolonged Nirmatrelvir/Ritonavir Monotherapy Leading to Clinical and Virological Treatment Failure—a Case Report

Clinical Infectious Diseases, Год журнала: 2023, Номер 78(2), С. 352 - 355

Опубликована: Авг. 19, 2023

Abstract Resistance of SARS-CoV-2 to antivirals was shown develop in immunocompromised individuals receiving remdesivir. We describe an patient who treated with repeated and prolonged courses nirmatrelvir developed de-novo E166V/L50F mutations the Mpro region. These were associated clinical virological treatment failure.

Язык: Английский

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Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir

Nature Microbiology, Год журнала: 2024, Номер 9(4), С. 1075 - 1088

Опубликована: Март 29, 2024

Abstract Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir still needed, particularly individuals in whom less effective, the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of SARS-CoV-2 main protease (M pro ), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has constant 8.4 nM and suggests it dissociates about 12 times slower from M compared with nirmatrelvir. The crystal structure :RAY1216 complex covalently binds catalytic Cys145 through α-ketoamide group. In vitro using human ACE2 transgenic mouse models, activities against variants comparable those It also improved pharmacokinetics mice rats, suggesting could be used without ritonavir, which is co-administered been approved a single-component drug named ‘leritrelvir’ COVID-19 treatment China.

Язык: Английский

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SARS-CoV-2 Drug Resistance and Therapeutic Approaches

Heliyon, Год журнала: 2025, Номер 11(2), С. e41980 - e41980

Опубликована: Янв. 1, 2025

Язык: Английский

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In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance

Science Advances, Год журнала: 2024, Номер 10(30)

Опубликована: Июль 24, 2024

To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against virus M

Язык: Английский

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The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19

Pharmaceutics, Год журнала: 2024, Номер 16(2), С. 217 - 217

Опубликована: Фев. 2, 2024

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms action some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. most effective drug approved date for treatment is PaxlovidTM, which combination two protease inhibitors, nirmatrelvir ritonavir. Nirmatrelvir reversible covalent peptidomimetic inhibitor main (Mpro) SARS-CoV-2, enzyme plays crucial role reproduction. In this combination, ritonavir serves as pharmacokinetic enhancer, it irreversibly inhibits cytochrome CYP3A4 responsible rapid metabolism nirmatrelvir, thereby increasing half-life bioavailability nirmatrelvir. tutorial review, we summarize development pharmaceutical chemistry aspects Paxlovid, covering evolution warhead design, synthesis mechanism well its inhibition mechanism. efficacy Paxlovid novel virus mutants also overviewed.

Язык: Английский

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Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 18, 2024

Язык: Английский

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An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

Science Translational Medicine, Год журнала: 2024, Номер 16(738)

Опубликована: Март 13, 2024

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing severity COVID-19, but presence resistance-conferring mutations sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized covalent hepatitis C virus inhibitor boceprevir (BPV) could serve basis for orally bioavailable inhibit SARS-CoV-2 M more efficiently than existing drugs. Performing structure-guided modifications BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, pharmacokinetics, therapeutic efficacy similar or superior to those NTV. A crucial feature ML2006a4 is derivatization ketoamide reactive group improves cell permeability bioavailability. Last, was found be less sensitive several cause resistance NTV ETV occur natural population. Thus, anticipatory design can preemptively address potential mechanisms expand treatment options variants.

Язык: Английский

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Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains

Antiviral Research, Год журнала: 2024, Номер 222, С. 105814 - 105814

Опубликована: Янв. 24, 2024

Since the start of SARS-CoV-2 pandemic, search for antiviral therapies has been at forefront medical research. To date, 3CLpro inhibitor nirmatrelvir (Paxlovid®) shown best results in clinical trials and greatest robustness against variants. A second protease inhibitor, ensitrelvir (Xocova®), developed. Ensitrelvir, currently Phase 3, was approved Japan under emergency regulatory approval procedure November 2022, is available since March 31, 2023. One limitations use monotherapies emergence resistance mutations. Here, we experimentally generated mutants resistant to vitro following repeating passages presence both antivirals. For molecules, demonstrated a loss sensitivity vitro. Using Syrian golden hamster infection model, showed that M49L mutation, multi-passage strain, confers high level vivo resistance. Finally, identified recent increase prevalence M49L-carrying sequences, which appears be associated with multiple repeated events may related Xocova® country 2022. These highlight strategic importance genetic monitoring circulating strains ensure treatments administered retain their full effectiveness.

Язык: Английский

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Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents

Biomolecules, Год журнала: 2024, Номер 14(7), С. 797 - 797

Опубликована: Июль 4, 2024

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it significant target for developing antiviral drugs. inhibition Mpro has emerged as promising approach therapeutic agents to treat COVID-19. This review explores structure protein and analyzes progress made understanding protein–ligand interactions inhibitors. It focuses on binding kinetics, origin, chemical these provides in-depth analysis recent clinical trials involving covalent non-covalent inhibitors emerging dual targeting Mpro. By integrating findings from literature ongoing trials, this captures current state research into inhibitors, offering comprehensive challenges directions their future development anti-coronavirus agents. information new insights inspiration medicinal chemists, paving way more effective novel COVID-19 therapies.

Язык: Английский

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The evaluation of risk factors for prolonged viral shedding during anti-SARS-CoV-2 monoclonal antibodies and long-term administration of antivirals in COVID-19 patients with B-cell lymphoma treated by anti-CD20 antibody

BMC Infectious Diseases, Год журнала: 2024, Номер 24(1)

Опубликована: Июль 22, 2024

Abstract Background The global impact of the coronavirus disease 2019 (COVID-19) pandemic has resulted in significant morbidity and mortality. Immunocompromised patients, particularly those treated for B-cell lymphoma, have shown an increased risk persistent infection with SARS-CoV-2 severe outcomes Multi-mutational variants can arise during course such cases COVID-19. No optimal, decisive strategy is currently available patients that allows clinicians to sustain viral clearance, determine optimal timing stop treatment, prevent virus reactivation. We introduced a novel treatment combining antivirals, neutralizing antibodies, genomic analysis frequent monitoring spike-specific antibody load immunocompromised COVID-19 infection. aim this retrospective study was report evaluate efficacy our lymphoma Methods This descriptive had no controls. Patients previously receiving immunotherapy including anti-CD20 diagnosed as having infection, hospital after January 2022 were included. selected anti-SARS-CoV-2 monoclonal antibodies according subvariants. Every 5 days, tested by RT-PCR, antivirals continued until shedding confirmed. Primary outcome elimination. Independent predictors prolonged time determined multivariate Cox regression. Results Forty-four included study. Thirty-five received rituximab, 19 obinutuzumab, 26 bendamustine. Median duration 10 (IQR, 10–20) days; 22 combination antiviral therapy. 16 critical 2. All survived, confirmed at median 28 19–38) days. Bendamustine use or within 1 year last multiple lines significantly shedding. Conclusions Among 44 consecutive treated, long-term administration drugs, switching, therapy elimination 100% survival. use, independent time.

Язык: Английский

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