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

ACS Central Science, Год журнала: 2023, Номер 9(8), С. 1658 - 1669

Опубликована: Июль 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.

Язык: Английский

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Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants

Metabolites, Год журнала: 2023, Номер 13(2), С. 309 - 309

Опубликована: Фев. 20, 2023

The nucleoside analog β-D-N4-hydroxycytidine is the active metabolite of prodrug molnupiravir and accepted as an efficient drug against COVID-19. Molnupiravir targets RNA-dependent RNA polymerase (RdRp) enzyme, which responsible for replicating viral genome during replication process certain types viruses. It works by disrupting normal function RdRp causing it to make mistakes genome. These can prevent from being transcribed, converted into a complementary DNA template, translated, or functional protein. By these crucial steps in process, effectively inhibit virus reduce its ability cause disease. This review article sheds light on impact SARS-CoV-2 variants concern, such delta, omicron, hybrid/recombinant variants. detailed mechanism molecular interactions using docking dynamics have also been covered. safety tolerability patients with comorbidities emphasized.

Язык: Английский

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Combination regimen of nirmatrelvir/ritonavir and molnupiravir for the treatment of persistent SARS-CoV-2 infection: A case report and a scoping review of the literature

International Journal of Infectious Diseases, Год журнала: 2023, Номер 133, С. 53 - 56

Опубликована: Май 5, 2023

Immunocompromised patients still experience unpredictable courses of COVID-19, despite that effective vaccines and drugs against SARS-CoV-2 are now available. Antiviral combination regimens may have a role in infection immunocompromised hosts, but current knowledge is limited. We describe the case 73-year-old Italian man affected by follicular lymphoma with persistent who was successfully treated co-administration oral antivirals (10-day molnupiravir nirmatrelvir/ritonavir). The therapy well tolerated both from clinical biochemical standpoint, no signs toxicity. also performed scoping review, to sum up available on combined antiviral including remdesivir, molnupiravir, or nirmatrelvir/ritonavir. Pending further studies larger cohorts patients, our report consistent pre-clinical data, supporting possible use selected difficult-to-treat COVID-19 cases.

Язык: Английский

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Early combination therapy of COVID-19 in high-risk patients

Infection, Год журнала: 2023, Номер 52(3), С. 877 - 889

Опубликована: Ноя. 29, 2023

Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this certainty. Dual therapies may therefore have a synergistic effect.

Язык: Английский

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COVID-19 therapeutics

Clinical Microbiology Reviews, Год журнала: 2024, Номер 37(2)

Опубликована: Май 21, 2024

SUMMARYSince the emergence of COVID-19 in 2020, an unprecedented range therapeutic options has been studied and deployed. Healthcare providers have multiple treatment approaches to choose from, but efficacy those often remains controversial or compromised by viral evolution. Uncertainties still persist regarding best therapies for high-risk patients, drug pipeline is suffering fatigue shortage funding. In this article, we review antiviral activity, mechanism action, pharmacokinetics, safety therapies. Additionally, summarize evidence from randomized controlled trials on various antivirals discuss unmet needs which should be addressed.

Язык: Английский

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B-cell-depleted patients with persistent SARS-CoV-2 infection: combination therapy or monotherapy? A real-world experience

Frontiers in Medicine, Год журнала: 2024, Номер 11

Опубликована: Фев. 29, 2024

Objectives The aim of the study was to describe a cohort B-cell-depleted immunocompromised (IC) patients with prolonged or relapsing COVID-19 treated monotherapy combination therapy. Methods This is multicenter observational retrospective conducted on IC consecutively hospitalized SARS-CoV-2 infection from November 2020 January 2023. subjects were stratified according anti-SARS-CoV-2 therapy received. Results Eighty-eight enrolled, 19 under and 69 population had history immunosuppression (median 2 B-cells/mm 3 , IQR 1–24 cells), residual hypogammaglobulinemia observed in 55 patients. A reduced length hospitalization time negative molecular nasopharyngeal swab (NPS) versus group observed. In univariable multivariable analyses, percentage change rate days NPS negativity showed significant reduction receiving compared those monotherapy. Conclusion persistent patients, it essential explore new therapeutic strategies such as multi-target (antiviral double antiviral plus antibody-based therapies) avoid viral shedding and/or severe infection.

Язык: Английский

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Emerging SARS-CoV-2 Resistance After Antiviral Treatment

JAMA Network Open, Год журнала: 2024, Номер 7(9), С. e2435431 - e2435431

Опубликована: Сен. 25, 2024

Importance Previous studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this arises and its association with posttreatment virologic rebound is not well understood. Objective To examine the prevalence of emergent antiviral after nirmatrelvir treatment rebound. Design, Setting, Participants This cohort study enrolled outpatient adults acute COVID-19 infection from May 2021 October 2023. were divided into those who received therapy did not. The was conducted at a multicenter health care system Boston, Massachusetts. Exposure Treatment regimen, including none, remdesivir. Main Outcomes Measures primary outcome resistance, defined as detection mutations, which present baseline, previously associated decreased efficacy, emerged during or completion participant’s treatment. Next-generation sequencing used detect low frequency down 1% total viral population. Results Overall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) included. Compared 63 untreated individuals, 79 older more commonly immunosuppressed. After RNA participants’ anterior nasal swabs, detected 9 individuals (11.4%) compared 2 (3.2%) ( P = .09). Among treated immunosuppressed had highest emergence (5 22 [22.7%]), significantly greater than (2 [3.1%]) .01). Similar rates found (3 23 [13.0%]) vs (6 [10.7%]) .86). Most these (10 11 [90.9%]) frequencies (&amp;lt;20% population) reverted wild type subsequent time points. Emerging remdesivir only 14 [14.3%]) but similarly transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence increased United States authorization nirmatrelvir. Conclusions Relevance In participants, treatment-emergent detected, especially However, generally transient nature, suggesting risk for spread community current variants drug usage patterns.

Язык: Английский

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Bioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens

iScience, Год журнала: 2024, Номер 27(3), С. 109049 - 109049

Опубликована: Янв. 30, 2024

Язык: Английский

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Favipiravir and Ribavirin protect immunocompetent mice from lethal CCHFV infection

Antiviral Research, Год журнала: 2023, Номер 218, С. 105703 - 105703

Опубликована: Авг. 21, 2023

Язык: Английский

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Aprotinin—Drug against Respiratory Diseases

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(13), С. 11173 - 11173

Опубликована: Июль 6, 2023

Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, widely used as antithrombotic and anti-inflammatory drug cardiac noncardiac surgeries for reduction of bleeding thus limiting the need blood transfusion. The ability to inhibit proteolytic activation some viruses leads its use antiviral prevention treatment acute respiratory virus infections. However, due incompetent interpretation several clinical trials followed by incredible controversy literature, usage nearly stopped decade worldwide. In 2015-2020, after re-analysis these trials' data restrictions were lifted This review discusses mechanisms action summarizes current knowledge prospective regarding diseases caused RNA-containing viruses, including influenza SARS-CoV-2 or part combination treatment.

Язык: Английский

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