SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs DOI Creative Commons
Sho Iketani, David D. Ho

Cell chemical biology, Год журнала: 2024, Номер 31(4), С. 632 - 657

Опубликована: Апрель 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Язык: Английский

Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review DOI Creative Commons
Xin Li, Yongcheng Song

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 260, С. 115772 - 115772

Опубликована: Авг. 28, 2023

Язык: Английский

Процитировано

52
SARS-CoV-2 Drug Resistance and Therapeutic Approaches DOI Creative Commons

Sania Batool,

Santosh Chokkakula, Ju Hwan Jeong

и другие.

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

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

3
The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitorin vitroand confer resistance to nirmatrelvir DOI Creative Commons
Dirk Jochmans, Liu C,

Kim Donckers

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Июнь 7, 2022

Abstract 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 > 20x increase EC 50 values nirmatrelvir (PF-07321332) PF-00835231. While two single (E166A provide low-level resistance inhibitors biochemical assay, triple mutant results highest levels (6x 72x). 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 resistant viruses. In order guide use novel antivirals it essential understand risk characterize changes genes proteins. this work, we describe time pathway allows develop against . characteristics may predictive situation. our work management COVID-19 next generation inhibitors.

Язык: Английский

Процитировано

42
A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part) DOI Creative Commons
Hiroshi Yotsuyanagi, Norio Ohmagari, Yohei Doi

и другие.

Medicine, Год журнала: 2023, Номер 102(8), С. e33024 - e33024

Опубликована: Фев. 22, 2023

Limited treatment options exist for patients with mild-to-moderate coronavirus disease 2019 (COVID-19), irrespective of vaccination history or risk status. Ensitrelvir is a novel oral severe acute respiratory syndrome 2 (SARS-CoV-2) 3C-like (3CL) protease inhibitor. While phase studies ensitrelvir have demonstrated promising results in treating COVID-19, evaluation its clinical efficacy due to shifting status and emergence the Omicron variant represents significant challenges. Here, we describe protocol 3 study designed evaluate safety regardless history.This multicenter, randomized, double-blind, placebo-controlled, study. Patients COVID-19 within 120 hours from onset will be randomized 1:1:1 ratio into arms-ensitrelvir 125 mg (375 loading dose on Day 1), 250 (750 placebo. The interventions administered orally, once-daily, 5 days. primary endpoint time resolution symptoms (stuffy runny nose, sore throat, cough, feeling hot feverish, low energy tiredness), key secondary endpoints include change baseline 4 amount SARS-CoV-2 viral ribonucleic acid (RNA) first negative titer. population <72 randomization and, subsequently, entire patient (<120 hours) group. Closed testing procedure used both populations. All assessments adverse events (AE) reported.In post hoc analysis 2b study, compared placebo, reduced COVID-19. Through this intend validate establish

Язык: Английский

Процитировано

39
In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir DOI Creative Commons
Maki Kiso, Seiya Yamayoshi, Shun Iida

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 15, 2023

Ensitrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro or Nsp5), is clinically useful against including its omicron variants. Since most subvariants have reduced sensitivity to monoclonal antibody therapies, resistance other antivirals inhibitors such as ensitrelvir major public health concern. Here, repeating passages of in the presence revealed M49L and E166A substitutions Nsp5 are responsible for ensitrelvir. Both vitro virus growth absence The combination allowed largely evade suppressive effect vitro. possessing Nsp5-M49L showed similar pathogenicity wild-type virus, whereas Nsp5-E166A Nsp5-M49L/E166A slightly attenuated. Ensitrelvir treatment hamsters infected with was ineffective; however, nirmatrelvir molnupiravir effective. Therefore, it important closely monitor emergence ensitrelvir-resistant variants guide selection.

Язык: Английский

Процитировано

39
Molecular mechanism of ensitrelvir inhibiting SARS-CoV-2 main protease and its variants DOI Creative Commons
Meng-Meng Lin, Xudong Zeng, Yinkai Duan

и другие.

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Июль 5, 2023

Abstract SARS-CoV-2 poses an unprecedented threat to the world as causative agent of COVID-19 pandemic. Among a handful therapeutics developed for prevention and treatment infection, ensitrelvir is first noncovalent nonpeptide oral inhibitor targeting main protease (M pro ) SARS-CoV-2, which recently received emergency regulatory approval in Japan. Here we determined 1.8-Å structure M complex with ensitrelvir, revealed that targets substrate-binding pocket , specifically recognizing its S1, S2, S1' subsites. Further, our comprehensive biochemical structural data have demonstrated even though nirmatrelvir (an FDA-approved drug) belong different types inhibitors, both them remain be effective against s from all five variants concern, suggesting bona fide broad-spectrum target. The molecular mechanisms uncovered this study provide basis future design.

Язык: Английский

Процитировано

36
Nirmatrelvir and COVID-19: development, pharmacokinetics, clinical efficacy, resistance, relapse, and pharmacoeconomics DOI
Daniele Focosi, Scott A. McConnell, Shmuel Shoham

и другие.

International Journal of Antimicrobial Agents, Год журнала: 2023, Номер 61(2), С. 106708 - 106708

Опубликована: Янв. 2, 2023

Язык: Английский

Процитировано

31
Evaluation of the Drug–Drug Interaction Potential of Ensitrelvir Fumaric Acid with Cytochrome P450 3A Substrates in Healthy Japanese Adults DOI Creative Commons
Ryosuke Shimizu, Takuhiro Sonoyama, Takahiro Fukuhara

и другие.

Clinical Drug Investigation, Год журнала: 2023, Номер 43(5), С. 335 - 346

Опубликована: Май 1, 2023

Management of drug–drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor SARS-CoV-2 infection is crucial. A previous clinical DDI study ensitrelvir with midazolam, index cytochrome P450 (CYP) 3A substrate, demonstrated that given 5 days orally loading/maintenance dose 750/250 mg acted as strong CYP3A inhibitor. The objectives this were to investigate the effect on pharmacokinetics substrates, dexamethasone, prednisolone and assess pharmacokinetics, safety, tolerability following multiple-dose administration ensitrelvir. This was Phase 1, multicenter, single-arm, open-label in healthy Japanese adult participants. effects multiple doses fasted state prednisolone, midazolam investigated. Ensitrelvir administered from Day 1 through 5, dexamethasone cohorts whereas 375/125 cohort. Either or alone (Day − 2) combination 5) each cohorts. Additionally, Days 9 14. pharmacokinetic parameters calculated based their plasma concentration data non-compartmental analysis. In safety assessments, nature, frequency, severity treatment-emergent adverse events evaluated recorded. area under concentration-time curve (AUC) ratio 3.47-fold compared corresponding values 2 diminished over time after last No clinically meaningful observed prednisolone. AUC 6.77-fold suggesting at strongly inhibits similar mg. new signals reported during study. inhibitory confirmed time. addition, showed potential These findings can be used recommendation prescribing regard concomitant medications. Japan Registry Clinical Trials identifier: jRCT2031210202.

Язык: Английский

Процитировано

27
Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2in vitroandin vivo DOI Creative Commons
Takayuki Kuroda, Haruaki Nobori,

Keita Fukao

и другие.

Journal of Antimicrobial Chemotherapy, Год журнала: 2023, Номер 78(4), С. 946 - 952

Опубликована: Янв. 26, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become established in the human population, making need to develop safe and effective treatments critical. We have developed small-molecule antiviral ensitrelvir, which targets 3C-like (3CL) protease of SARS-CoV-2. This study evaluated vitro vivo efficacy ensitrelvir compared with that another SARS-CoV-2 3CL PI, nirmatrelvir.

Язык: Английский

Процитировано

25
A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations DOI Creative Commons
Jin Ou, Eric M. Lewandowski, Yanmei Hu

и другие.

PLoS Pathogens, Год журнала: 2023, Номер 19(8), С. e1011592 - e1011592

Опубликована: Авг. 31, 2023

The SARS-CoV-2 main protease (M pro ) is a major therapeutic target. M inhibitor, nirmatrelvir, the antiviral component of Paxlovid, an orally available treatment for COVID-19. As inhibitor use increases, drug resistant mutations will likely emerge. We have established non-pathogenic system, in which yeast growth serves as approximation activity, enabling rapid identification mutants with altered enzymatic activity and sensitivity. E166 residue known to be potential hot spot resistance assays identified substitutions conferred strong nirmatrelvir others that compromised activity. On other hand, N142A P132H mutation, carried by Omicron variant, caused little no change response Standard confirmed results. In turn, we solved structures E166R, E166N, providing insights into how arginine may drive while asparagine leads reduced work presented here help characterize novel variants arise antivirals become more widely used.

Язык: Английский

Процитировано

24