Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19

JAMA Network Open, Год журнала: 2024, Номер 7(2), С. e2354991 - e2354991

Опубликована: Фев. 9, 2024

Importance Treatment options for COVID-19 are warranted irrespective of the presence risk factors severe disease. Objective To assess efficacy and safety ensitrelvir in patients with mild to moderate COVID-19. Design, Setting, Participants This phase 3 part a 2/3, double-blind, placebo-controlled randomized clinical trial was conducted from February 10 July 10, 2022, 28-day follow-up period, at 92 institutions Japan, Vietnam, South Korea. Patients (aged 12 <70 years) within 120 hours positive viral test results were studied. Interventions (1:1:1) receive 125 mg once-daily (375 on day 1), 250 (750 or placebo 5 days. Main Outcomes Measures The primary end point time resolution composite characteristic symptoms SARS-CoV-2 Omicron infection, assessed using Peto-Prentice generalized Wilcoxon stratified by vaccination history. Virologic also assessed. Results A total 1821 randomized, whom 1030 (347 125-mg group, 340 250-mg 343 group) less than 72 disease onset (primary analysis population). mean (SD) age this population 35.2 (12.3) years, 552 (53.6%) men. significant difference observed between group ( P = .04 test). median approximately 1 (167.9 vs 192.2 hours; difference, −24.3 95% CI, −78.7 11.7 hours). Adverse events 267 604 (44.2%) 321 599 150 605 (24.8%) which included decrease high-density lipoprotein level (188 [31.1%] 231 [38.6%] 23 [3.8%] group). No treatment-related serious adverse reported. Conclusions Relevance In trial, treatment reduced typical compared treated onset; absolute day. Ensitrelvir demonstrated antiviral without new concerns. Generalizability populations outside Asia should be confirmed. Trial Registration Japan Registry Clinical Trials Identifier: jRCT2031210350

Язык: Английский

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In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir

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

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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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Ensitrelvir Fumaric Acid: First Approval

Drugs, Год журнала: 2024, Номер 84(6), С. 721 - 728

Опубликована: Май 25, 2024

Язык: Английский

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Synthetic Approaches to the New Drugs Approved During 2022

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(6), С. 4376 - 4418

Опубликована: Март 15, 2024

In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes synthetic approach demonstrated on largest scale for each drug based patent or primary literature. The routes highlight practical methods to construct molecules, sometimes manufacturing scale, access drugs. Ten additional in 2021 one 2020 are included that not covered previous year's review.

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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Safety and Efficacy of Ephedrine Alkaloids-Free Ephedra Herb Extract (EFE) for Mild COVID-19: A Double-Blind, Placebo-Controlled, Randomized Comparative Trial

Microorganisms, Год журнала: 2025, Номер 13(3), С. 641 - 641

Опубликована: Март 12, 2025

Several Ephedra Herb-containing Kampo medicines are common initial treatments for various infections; however, the ephedrine alkaloids in Herb can cause side effects by stimulating adrenergic receptors. Accordingly, an alkaloids-free Extract (EFE) has been developed. This study aimed to evaluate whether EFE be used effectively and safely patients with mild coronavirus disease 2019 (COVID-19). We randomized COVID-19 receive equivalent 6 g of per day or a placebo 14 days. The primary efficacy endpoint was non-aggravation rate up Day 15. allocated 41 40 groups, respectively. All participants were included mITT safety analysis populations [male ratio, mean age: 31.7%, 42.0 years (EFE); 17.5%, 43.2 (placebo)]. 15 100.0% 94.6% group, respectively, no between-group difference. number days improvement nausea symptoms significantly shorter group. One patient group discontinued trial due effect. Although demonstrated COVID-19, it did not show superior compared other than nausea.

Язык: Английский

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Promising Experimental Anti-SARS-CoV-2 Agent “SLL-0197800”: The Prospective Universal Inhibitory Properties against the Coming Versions of the Coronavirus

ACS Omega, Год журнала: 2023, Номер 8(39), С. 35538 - 35554

Опубликована: Сен. 18, 2023

Isoquinoline derivatives having some nucleosidic structural features are considered as candidate choices for effective remediation of the different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their following disease, disease 2019 (COVID-19). SLL-0197800 is a recently discovered isoquinoline compound with potential strong universal anticoronaviral activities against SARS-CoV-2 its previous strains. nonspecifically hits main protease (Mpro) enzyme coronaviruses. Herein in present study, we tested probability findings this experimental agent to be extended comprise any through concurrently disrupting mutable-less replication enzymes like RNA-dependent RNA polymerase (RdRp) protein well 3'-to-5' exoribonuclease (ExoN) protein. The vitro anti-RdRp/ExoN assay revealed potent inhibitory on coronaviral minute values anti-RdRp EC50 (about 0.16 0.27 μM, respectively). preliminary silico outcomes significantly supported these biochemical findings. To put it simply, important results extension efforts greatly reinforce extend SLL-0197800's preceding findings, showing that restraining/blocking actions (i.e., activities) novel investigational anti-SARS-CoV-2 Mpro could other copying multiplication such RdRp ExoN, highlighting use coming versions homicidal (if any), i.e., revealing probable nonspecific qualities golden drug nearly strain, instance, SARS-CoV-3.

Язык: Английский

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On the origins of SARS-CoV-2 main protease inhibitors

RSC Medicinal Chemistry, Год журнала: 2023, Номер 15(1), С. 81 - 118

Опубликована: Окт. 13, 2023

In order to address the world-wide health challenge caused by COVID-19 pandemic, 3CL protease/SARS-CoV-2 main protease (SARS-CoV-2-M

Язык: Английский

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Ritonavir: 25 Years’ Experience of Concomitant Medication Management. A Narrative Review

Infectious Diseases and Therapy, Год журнала: 2024, Номер 13(5), С. 1005 - 1017

Опубликована: Апрель 12, 2024

Ritonavir is a potent inhibitor of the cytochrome P450 3A4 enzyme and commonly used as pharmacokinetic (PK) enhancer in antiviral therapies because it increases bioavailability concomitantly administered antivirals. Decades experience with ritonavir-enhanced HIV and, more recently, COVID-19 demonstrate that boosting doses ritonavir are well tolerated, an established safety profile. The mechanisms PK enhancement by result potential for drug–drug interactions (DDIs) several classes drugs, thus making co-medication management important consideration enhanced therapies. However, rates DDIs contraindicated medications low, suggesting these risks manageable infectious disease specialists who have use enhancers. In this review, we provide overview ritonavir's action describe approaches resources available to mitigate adverse events manage concomitant medication both chronic short-term settings.

Язык: Английский

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