Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir DOI Creative Commons
Laura Krismer, Helge Schöppe, Stefanie Rauch

et al.

npj Viruses, Journal Year: 2024, Volume and Issue: 2(1)

Published: June 24, 2024

Abstract The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring ability efficiently spread among humans and become pandemic. Its high mortality rate of up 35% absence effective targeted therapies call for development antiviral drugs this pathogen. Since beginning SARS-CoV-2 pandemic, extensive research focused on identifying protease inhibitors treatment SARS-CoV-2. Our intention was therefore assess whether these are viable options combating MERS-CoV. To that end, we used previously established assays quantify inhibition SARS-CoV-2, main proteases. Nirmatrelvir inhibited several proteases, whereas ensitrelvir less broadly active. simulate nirmatrelvir’s clinical use against subsequent resistance development, applied a safe, surrogate virus-based system. Using virus, selected hallmark mutations SARS-CoV-2-M pro , such as T21I, M49L, S144A, E166A/K/V L167F. In current study, pool MERS-CoV-M mutants, characterized modelled steric effect catalytic site mutants S142G, S142R, S147Y A171S.

Language: Английский

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

et al.

Clinical Drug Investigation, Journal Year: 2023, Volume and Issue: 43(5), P. 335 - 346

Published: May 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.

Language: Английский

Citations

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

et al.

Journal of Antimicrobial Chemotherapy, Journal Year: 2023, Volume and Issue: 78(4), P. 946 - 952

Published: Jan. 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.

Language: Английский

Citations

25
An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations DOI
Michael Westberg, Yichi Su, Xinzhi Zou

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(738)

Published: March 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.

Language: Английский

Citations

12
Real-World Effectiveness of Ensitrelvir in Reducing Severe Outcomes in Outpatients at High Risk for COVID-19 DOI Creative Commons
Takahiro Takazono, Satoki Fujita,

Takuji Komeda

et al.

Infectious Diseases and Therapy, Journal Year: 2024, Volume and Issue: 13(8), P. 1821 - 1833

Published: June 28, 2024

This study aimed to evaluate the effectiveness of ensitrelvir, an oral antiviral, in reducing hospitalization risk outpatients at high-risk for severe COVID-19 during Omicron era. was a retrospective using large Japanese health insurance claims database. It included symptoms who received their first diagnosis between November 2022 and July 2023. The aged ≥ 18 years. primary endpoint all-cause 4-week period from date outpatient medication, comparing ensitrelvir group (n = 5177) no antiviral treatment 162,133). ratio difference were evaluated after adjusting patient background distribution by inverse probability weight (IPTW) method. Secondary endpoints incidence respiratory heart rate monitoring, oxygen therapy, ventilator use, intensive care admission, death. 167,385) 167,310) IPTW adjustment 0.629 [95% confidence interval (CI) 0.420, 0.943]. - 0.291 CI 0.494, 0.088]. both monitoring therapy lower group. Ventilator death difficult assess because limited events. significantly than group, suggesting is effective patients COVID-19.

Language: Английский

Citations

11
Ensitrelvir Fumaric Acid: First Approval DOI

Yahiya Y. Syed

Drugs, Journal Year: 2024, Volume and Issue: 84(6), P. 721 - 728

Published: May 25, 2024

Language: Английский

Citations

10
SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs DOI Creative Commons
Sho Iketani, David D. Ho

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(4), P. 632 - 657

Published: April 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,

Language: Английский

Citations

9
Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial DOI Creative Commons
Hongzhou Lu, George Zhang,

John Mao

et al.

EClinicalMedicine, Journal Year: 2024, Volume and Issue: 71, P. 102582 - 102582

Published: April 10, 2024

GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed evaluate the safety of administered plus Ritonavir patients with coronavirus disease 2019 (COVID-19) infected emerging XBB non-XBB variants.

Language: Английский

Citations

8
Proof-of-concept studies with a computationally designed M pro inhibitor as a synergistic combination regimen alternative to Paxlovid DOI Creative Commons
Christina Papini, Irfan Ullah, Amalendu P. Ranjan

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(17)

Published: April 15, 2024

As the SARS-CoV-2 virus continues to spread and mutate, it remains important focus not only on preventing through vaccination but also treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a main protease (M pro ) DAA, has been significant for treatment patients. A limitation this however, is that antiviral component, nirmatrelvir, rapidly metabolized requires inclusion CYP450 3A4 metabolic inhibitor, ritonavir, boost levels active drug. Serious drug–drug interactions can occur Paxlovid patients who are taking other medications by CYP4503A4, particularly transplant or otherwise immunocompromised most at risk development severe symptoms. Developing an alternative improved pharmacological properties critical these By using computational structure-guided approach, we were able optimize 100 250 μM screening hit potent nanomolar inhibitor lead compound, Mpro61. In study, further evaluate Mpro61 as starting examination its mode binding M . vitro profiling established lack off-target effects, inhibition, well potential synergy currently approved alternate antiviral, molnupiravir. Development subsequent testing capsule formulation oral dosing in B6-K18-hACE2 mice demonstrated favorable properties, efficacy, molnupiravir, complete recovery from challenge SARS-CoV-2, establishing promising preclinical candidate.

Language: Английский

Citations

8
Ensitrelvir for the Treatment of Nonhospitalized Adults with COVID-19: Results from the SCORPIO-HR, Phase 3, Randomized, Double-blind, Placebo-Controlled Trial DOI Creative Commons
Anne F. Luetkemeyer, Kara W. Chew,

Stuart R. Lacey

et al.

Clinical Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

Ensitrelvir, a severe acute respiratory syndrome coronavirus-2 main protease inhibitor, has demonstrated clinical and virologic efficacy in previous studies. In this global phase 3 trial, nonhospitalized adults with mild-to-moderate coronavirus disease 2019 (COVID-19) symptom onset within 5 days were randomized (1:1) to receive once-daily ensitrelvir (375 mg day 1, 125 2-5) or blinded matching placebo. The primary endpoint was the restricted mean time sustained (≥2 days) resolution of 15 COVID-19 symptoms, recorded participant daily diaries, through 29 participants starting treatment after onset. Virologic safety assessed. Of 2093 participants, 1888 started Mean 12.5 13.1 placebo, respectively (difference, -0.6 days; 95% confidence interval, -1.38 0.19; P = .14). On 4, reduced least-squares RNA by 0.72 log10 copies/mL more than placebo (95% 0.55-0.90). Among those positive viral cultures at enrollment, 274/287 (95.5%) ensitrelvir-treated versus 210/280 (75.0%) placebo-treated had negative on 4. rebound similar (<1.5%) between groups. proportion ≥1 adverse event (61.5%) (60.6%). No treatment-related serious events deaths occurred. Three (0.3%) 1 (0.1%) COVID-19-related hospitalizations 29. Despite evidence antiviral activity ensitrelvir, trial did not demonstrate significant difference resolution.

Language: Английский

Citations

1
Open Science Discovery of Potent Non-Covalent SARS-CoV-2 Main Protease Inhibitors DOI Creative Commons
Melissa L. Boby, D. Fearon, Matteo P. Ferla

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: Oct. 30, 2020

Abstract We report the results of COVID Moonshot , a fully open-science, crowd sourced, structure-enabled drug discovery campaign targeting SARS-CoV-2 main protease. discovered non-covalent, non-peptidic inhibitor scaffold with lead-like properties that is differentiated from current protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology chemistry. generated detailed map plasticity protease, extensive structure-activity relationships for multiple chemotypes, wealth biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>840 ligand-bound X-ray structures), assay (>10,000 measurements), synthesized molecules (>2,400 compounds) this were shared rapidly openly, creating rich open IP-free knowledgebase future anti-coronavirus discovery.

Language: Английский

Citations

53