An orally available P1’-5-fluorinated Mpro inhibitor blocks SARS-CoV-2 replication without booster and exhibits high genetic barrier DOI Creative Commons
Nobuyo Higashi‐Kuwata, Haydar Bulut, Hironori Hayashi

и другие.

PNAS Nexus, Год журнала: 2024, Номер 4(1)

Опубликована: Дек. 23, 2024

We identified a 5-fluoro-benzothiazole-containing small molecule, TKB272, through fluorine-scanning of the benzothiazole moiety, which more potently inhibits enzymatic activity SARS-CoV-2's main protease (Mpro) and effectively blocks infectivity replication all SARS-CoV-2 strains examined including Omicron variants such as SARS-CoV-2XBB1.5 SARS-CoV-2EG.5.1 than two Mpro inhibitors: nirmatrelvir ensitrelvir. Notably, administration ritonavir-boosted ensitrelvir causes drug-drug interactions warranting cautions due to their CYP3A4 inhibition, thereby limiting clinical utility. When orally administered, TKB272 blocked without ritonavir in B6.Cg-Tg(K18-hACE2)2-Prlmn/J-transgenic mice, comparably did nirmatrelvir. ancestral was propagated with vitro, highly nirmatrelvir-resistant E166V-carrying variant (SARS-CoV-2E166V-P14) readily emerged by passage 14; however, when no 25. SARS-CoV-2E166V showed some cross-resistance but substantially sensitive compound. X-ray structural analyses mass-spectrometric data that E166V substitution disrupts critical dimerization-initiating Ser1'-E166 interactions, nirmatrelvir's inhibition nevertheless forms tight binding Mpro's catalytic active sight even presence substitution. shows apparent genotoxicity tested micro-Ames test. Highly potent may serve COVID-19 therapeutic, overcome resistance existing inhibitors.

Язык: Английский

Distal protein-protein interactions contribute to nirmatrelvir resistance DOI Creative Commons
Eric M. Lewandowski, Xiujun Zhang, Haozhou Tan

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 1, 2025

SARS-CoV-2 main protease, Mpro, is responsible for processing the viral polyproteins into individual proteins, including protease itself. Mpro a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component Paxlovid). Resistance mutants identified clinically and in passage assays contain combination site mutations (e.g., E166V, E166A, L167F), which reduce inhibitor binding enzymatic activity, non-active P252L, T21I, L50F), restore fitness replication. To probe role rescue, here we use an triple mutant (L50F/E166A/L167F) that confers drug resistance with level similar to wild-type. By comparing peptide full-length protein substrates, demonstrate substrate involves more than residues site. Particularly, L50F other can enhance dimer-dimer interactions help place nsp5-6 at enzyme catalytic center. The structural activity data L50F, L50F/E166A/L167F, others underscore importance considering whole studying interactions, offers important insights function, development, design.

Язык: Английский

Процитировано

1
Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance DOI Creative Commons
Tin Phan, Ruy M. Ribeiro,

Gregory E. Edelstein

и другие.

Journal of Virology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 4, 2025

ABSTRACT In a subset of SARS-CoV-2-infected individuals treated with the antiviral nirmatrelvir-ritonavir, virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used mathematical model to describe longitudinal viral load dynamics 51 20 whom rebounded. Target cell preservation, either by robust innate immune response or initiation N-R near time symptom onset, coupled incomplete clearance, appears be main factor leading rebound. Moreover, occurrence is likely influenced treatment relative progression infection, earlier treatments higher chance A comparison an untreated cohort suggests that early nirmatrelvir-ritonavir may associated delay in onset adaptive response. Nevertheless, our demonstrates extending course 10-day regimen greatly diminish people mild-to-moderate COVID-19 and who at high risk severe disease. Altogether, results suggest some individuals, standard 5-day starting around completely eliminate virus. Thus, after ends, can if effective has fully developed. These findings on role target preservation clearance also offer possible explanation for other SARS-CoV-2. IMPORTANCE Nirmatrelvir-ritonavir initial reduction followed once stopped. show timing influence stops growth preserves cells but lead full adequately developed, remaining Our provide insights into help develop better strategies minimize possibility.

Язык: Английский

Процитировано

0
M49L and other drug resistance mutations emerging in individuals after administration of ensitrelvir in Japanese clinical settings DOI Creative Commons
Akira Inoue, Takaya Ichikawa, Daiki Wada

и другие.

Antiviral Research, Год журнала: 2025, Номер 236, С. 106118 - 106118

Опубликована: Фев. 17, 2025

Язык: Английский

Процитировано

0
Cost-effectiveness Analysis of Nirmatrelvir/Ritonavir for COVID-19 Among Individuals at High Risk: A Modeling Study DOI Creative Commons
Emma Birnie, Magda Vergouwe, Brent Appelman

и другие.

Open Forum Infectious Diseases, Год журнала: 2025, Номер 12(4)

Опубликована: Март 26, 2025

Abstract Background To prevent severe disease, nirmatrelvir/ritonavir (nirmatrelvir/r) is administered to individuals infected with SARS-CoV-2 who are at high risk, and it currently priced approximately $1375 in the Netherlands. We aim evaluate health outcomes cost-effectiveness of nirmatrelvir/r among patients risk disease. Methods used a decision-analytic model parameterized clinical care utilization data from were between September 2021 November 2023. assumed baseline event rates 1% for hospitalization 0.05% intensive unit admission. Nirmatrelvir/r-related factors varied. Costs collected third-party payer’s perspective, threshold was <$88 000 per quality-adjusted life-year gained. Sensitivity analyses performed account uncertainties. Results This study included 949 SARS-CoV-2. The sample had median age 65 years (IQR, 53–75), 416 (44%) participants female. Comorbidities obesity (25%), hematologic malignancy (21%), solid organ/stem cell transplantation (17%), immunosuppressive medication use (47%). With an low effectiveness, could reduce hospitalizations deaths (relative reduction, 21% 44%, respectively). relative reductions 89% 90% calculated deaths. Higher hospital admission positively influenced thresholds. Nirmatrelvir/r cost-effectively <$512 effectiveness <$1071 effectiveness. Conclusions current hospitalization, has potential, not only COVID-19 but do so drug price reduction 22% 63%. These findings relevant policy makers physicians emphasize importance reevaluating pricing. Clinical Trials Registration NCT05195060 (ClinicalTrials.gov).

Язык: Английский

Процитировано

0
Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance DOI Creative Commons
Tin Phan, Ruy M. Ribeiro,

Gregory E. Edelstein

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 16, 2024

Abstract In a subset of SARS-CoV-2 infected individuals treated with the oral antiviral nirmatrelvir-ritonavir, virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used mathematical model to describe longitudinal viral load dynamics 51 20 whom rebounded. Target cell preservation, either by robust innate immune response or initiation nirmatrelvir-ritonavir near time symptom onset, coupled incomplete clearance, appear be main factors leading rebound. Moreover, occurrence is likely influenced treatment relative progression infection, earlier treatments higher chance Finally, our demonstrates that extending course treatment, in particular 10-day regimen, may greatly diminish risk for people mild-to-moderate COVID-19 and who at high severe disease. Altogether, results suggest some individuals, standard 5-day starting around onset completely eliminate virus. Thus, after ends, can if an effective adaptive has fully developed. These findings on role target preservation clearance also offer possible explanation other SARS-CoV-2. Importance Nirmatrelvir-ritonavir initial reduction followed once stopped. show timing influence stops growth preserves cells but lead full adequately developed, remaining Our provide insights into help develop better strategies minimize possibility.

Язык: Английский

Процитировано

1
Antiviral Stewardship in Transplantation DOI Creative Commons

Sruthi Bonda,

Sonya Trinh, Jonathan Hand

и другие.

Viruses, Год журнала: 2024, Номер 16(12), С. 1884 - 1884

Опубликована: Дек. 5, 2024

Though antimicrobial stewardship programs (ASPs) are required for hospitals, the involvement of transplant recipients in programmatic interventions, protocols, and metrics has historically been limited. there is a growing interest studying practices patients, optimal have not clearly established. A component ASPs, antiviral (AVS), specifically targeting cytomegalovirus (CMV), more recently described. Understanding AVS opportunities interventions particularly important recipients, given morbidity mortality associated with viral infections, challenging clinical syndromes, ultrasensitive molecular diagnostic assays, resistance, costs disease medications, as well drug toxicities. This review highlights CMV, EBV, HSV, VZV, SARS-CoV-2, respiratory syncytial virus, BK polyomavirus patients.

Язык: Английский

Процитировано

0
Independent FDA Analyses of Nirmatrelvir/Ritonavir Resistance in the Phase 2/3 Trials EPIC-HR and EPIC-SR DOI Creative Commons
Jonathan Rawson, Eric Donaldson,

Julian J. O’Rear

и другие.

Clinical Infectious Diseases, Год журнала: 2024, Номер unknown

Опубликована: Дек. 17, 2024

Abstract Background PAXLOVID consists of nirmatrelvir, an inhibitor SARS-CoV-2 main protease (Mpro), copackaged with ritonavir, a pharmacokinetic enhancer. Nirmatrelvir/ritonavir received emergency use authorization in the United States 2021 and was approved 2023. However, there is limited published information on clinical resistance to nirmatrelvir/ritonavir. Methods To investigate development nirmatrelvir/ritonavir treated patients, we analyzed baseline matching post-baseline next-generation sequencing data from 1,862 participants (912 nirmatrelvir/ritonavir, 950 placebo) EPIC-HR EPIC-SR, which were Phase 2/3, randomized, double-blind, placebo-controlled trials mild-to-moderate COVID-19. Potential resistance-associated substitutions (RAS) defined as those that enriched nirmatrelvir/ritonavir-treated or occurred at Mpro positions interest, using nonclinical data. sequence databases characterize temporal frequencies RAS circulating viruses. Results In EPIC-HR, included T21I (n=1), E166V (n=3), A173T T304I being clearest observed. no detected. not associated hospitalization death. Analyses did reveal concerning increases over time. Conclusions trials, emergence infrequent (<0.3%-1.1%). Surveillance currently indicate low frequency variants RAS. Collectively, these results provide most comprehensive analysis setting date. Viral sequences should continue be closely monitored identify potential nirmatrelvir/ritonavir-resistant variants.

Язык: Английский

Процитировано

0
An orally available P1’-5-fluorinated Mpro inhibitor blocks SARS-CoV-2 replication without booster and exhibits high genetic barrier DOI Creative Commons
Nobuyo Higashi‐Kuwata, Haydar Bulut, Hironori Hayashi

и другие.

PNAS Nexus, Год журнала: 2024, Номер 4(1)

Опубликована: Дек. 23, 2024

We identified a 5-fluoro-benzothiazole-containing small molecule, TKB272, through fluorine-scanning of the benzothiazole moiety, which more potently inhibits enzymatic activity SARS-CoV-2's main protease (Mpro) and effectively blocks infectivity replication all SARS-CoV-2 strains examined including Omicron variants such as SARS-CoV-2XBB1.5 SARS-CoV-2EG.5.1 than two Mpro inhibitors: nirmatrelvir ensitrelvir. Notably, administration ritonavir-boosted ensitrelvir causes drug-drug interactions warranting cautions due to their CYP3A4 inhibition, thereby limiting clinical utility. When orally administered, TKB272 blocked without ritonavir in B6.Cg-Tg(K18-hACE2)2-Prlmn/J-transgenic mice, comparably did nirmatrelvir. ancestral was propagated with vitro, highly nirmatrelvir-resistant E166V-carrying variant (SARS-CoV-2E166V-P14) readily emerged by passage 14; however, when no 25. SARS-CoV-2E166V showed some cross-resistance but substantially sensitive compound. X-ray structural analyses mass-spectrometric data that E166V substitution disrupts critical dimerization-initiating Ser1'-E166 interactions, nirmatrelvir's inhibition nevertheless forms tight binding Mpro's catalytic active sight even presence substitution. shows apparent genotoxicity tested micro-Ames test. Highly potent may serve COVID-19 therapeutic, overcome resistance existing inhibitors.

Язык: Английский

Процитировано

0