Synthesis and biological evaluation of novel peptidomimetic inhibitors of the coronavirus 3C-like protease

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 268, С. 116263 - 116263

Опубликована: Фев. 24, 2024

Язык: Английский

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Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (M^pro)

ACS Omega, Год журнала: 2024, Номер 9(32), С. 34196 - 34219

Опубликована: Авг. 2, 2024

Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), by SARS-CoV-2 its variants, further highlighted urgent need for development effective therapeutic agents. Currently, highly conserved broad-spectrum nature main proteases (M

Язык: Английский

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Effectiveness and safety of Sanhan Huashi granules versus nirmatrelvir–ritonavir in adult patients with COVID-19: A randomized, open-label, multicenter trial

Science Bulletin, Год журнала: 2024, Номер 69(12), С. 1954 - 1963

Опубликована: Апрель 23, 2024

Sanhan Huashi granules (SHG) demonstrated therapeutic effects against coronavirus disease 2019 (COVID-19) in observational studies. In order to compare the effectiveness and safety of SHG nirmatrelvir–ritonavir treating adults with mild-to-moderate COVID-19, we conducted a randomized, active-controlled, open-label, multi-center trial between February July 2023. The patients were randomized 1:1 ratio group group. A total 400 participants among which 200 ultimately received 198 nirmatrelvir–ritonavir. primary outcome was time sustained clinical recovery through day 28. significantly shortened median compared (6.0 [95% CI, 5.0 6.0] vs. 8.0 [CI,6.0 9.0] days; P = 0.001), particularly for individual symptoms including fever, sore throat, cough fatigue. No either died incidence severe COVID-19 showed no difference two groups. Participants who higher rate virus clearance on 5 those (46.4% [CI, 39.1 53.7] 65.6% 58.3 72.4]; < 0.001). Most adverse events mild both summary, superior shortening despite lower observed after days treatment (Chinese Clinical Trial Registry Identifier: ChiCTR2300067872).

Язык: Английский

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Efficacy and safety of SHEN26, a novel oral small molecular RdRp inhibitor for COVID-19 treatment: a multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial

Virology Journal, Год журнала: 2025, Номер 22(1)

Опубликована: Янв. 25, 2025

Abstract Background SHEN26 (ATV014) is an oral RNA-dependent RNA polymerase (RdRp) inhibitor with potential anti-SARS-CoV-2 activity. Safety, tolerability, and pharmacokinetic characteristics were verified in a Phase I study. This phase II study aimed to verify the efficacy safety of COVID-19 patients. Methods was multicenter randomized double-blind placebo-controlled Mild-to-moderate adult patients recruited randomly assigned high-dose (400 mg), low-dose (200 or placebo groups (1:1:1). The primary outcome measure “changes levels on Day seven (D7)”. second measures D3, D5, D10, D28,” “Time clearance virus.” Results A total 91 this between December 08, 2022, January 27, 2023. Twelve dropped out due lack examination results. Finally, data 79 (24 group, 31 200 mg 24 400 group) analyzed. No significant differences baseline observed groups. changes viral load significantly higher D3 ( P = 0.0119), D5 0.0120) group (vs. group), difference value achieved 1.06 log10 copies/mL 1.21 D5. found time administrating Administration did not enhance drug-related ADEs induce ADEs, ADE inducing drug withdrawal, dose reduction, death. Moreover, worsen renal function. Conclusions Our findings indicate better high mg) for treatment. These preliminary provide useful information working basis further verification development as novel small-molecule antiviral treating COVID-19.

Язык: Английский

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Synthesis and biological investigation of peptidomimetic SARS‐CoV‐2 main protease inhibitors bearing quinoline‐based heterocycles at P₃

Archiv der Pharmazie, Год журнала: 2025, Номер 358(1)

Опубликована: Янв. 1, 2025

Abstract In the last few years, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been cause of a worldwide pandemic, highlighting need for novel antiviral agents. The main protease (M pro ) SARS‐CoV‐2 was immediately identified as crucial enzyme viral replication and validated drug target. Here, we present design synthesis peptidomimetic M covalent inhibitors characterized by quinoline‐based P 3 moieties. Structure–activity relationships (SARs) were also investigated at 1 , well different warheads. binding modes designed assessed using X‐ray crystallographic molecular docking studies. tested their activities in cell‐based assays, results encouraging. SAR studies presented here can contribute to future improved addressing some current or prospective issues regarding currently used therapy.

Язык: Английский

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Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance

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

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Nucleoside reverse transcriptase inhibition enhances platelet production and megakaryocyte maturation in patients with COVID‐19

British Journal of Haematology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 10, 2025

Summary Coronavirus disease 2019 (COVID‐19) is a systemic infection frequently involving the haematopoietic system. Thrombocytopenia associated with increased risks of severe progression and mortality. Antiviral agents have shown much promise in decreasing viral load shortening time to resolution symptoms. However, their effect on platelet counts patients COVID‐19 remains unexplored. Therefore, we first performed retrospective study evaluate variation mass hospitalized high‐risk who were given either SARS‐CoV‐2 main protease inhibitor, nucleoside reverse transcriptase inhibitor or no antiviral agents. A total 177 included, among which 64 received azvudine, 12 nirmatrelvir–ritonavir 101 none. Compared those without treatment, significantly higher counts' increments observed receiving azvudine ( p = 0.001). Of note, this elevation was more profound group than that control < 0.001) 0.042). Subsequently, vitro experiments conducted investigate mechanism underlying activity azvudine. Results showed promoted polyploidization production MEG‐01 cell line. Although had minimal megakaryopoiesis, it could trigger release megakaryocytes presence spike‐membrane recombinant fusion protein not. Finally, RNA‐sequencing demonstrated azvudine‐treated exhibited marked increase VWF , TUBB1 GP1BA upregulated genes PI3K/AKT JAK/STAT signalling pathways. In conclusion, our findings indicated inhibition potentially enhances megakaryocyte maturation COVID‐19, suggesting new therapeutic option for thrombocytopenia.

Язык: Английский

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Development of antiviral drugs for COVID-19 in 2025: unmet needs and future challenges

Expert Review of Anti-infective Therapy, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

The success in the COVID-19 pandemic containment largely originated from vaccine- and infection-elicited immunity, with SARS-CoV-2 infection only marginally mitigated by availability of antiviral drugs. current lack effective prophylactic therapeutic agents immunocompromised patients highlights need for a radical change design both drug manufacturing clinical trials. In this review authors summarize their suggestions manufacturers, reviewing classes small molecule antivirals passive immunotherapies highlighting limitations unexploited potential. Molecular serological testing can improve appropriateness. Efficacy be improved combining different while preserving economical sustainability. Respiratory delivery should better investigated

Язык: Английский

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Identifying Exifone as a Dual-Target Agent Targeting Both SARS-CoV-2 3CL Protease and the ACE2/S-RBD Interaction Among Clinical Polyphenolic Compounds

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(5), С. 2243 - 2243

Опубликована: Март 2, 2025

The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has led to resistance against multiple disease 2019 (COVID-19) vaccines and therapeutic medications, making the development effective therapeutics SARS-CoV-2 a high priority. Studies have shown that bioactive polyphenols, particularly those with triphenol groups, can effectively inhibit activity 3-chymotrypsin-like protease (3CLpro). However, structural instability polyphenols necessitates further research. To address this, we conducted literature review identify compounds are either approved or currently undergoing clinical trials, assessing their potential 3CLpro. Exifone benserazide hydrochloride were identified as inhibitors 3CLpro among these compounds, using fluorescence resonance energy transfer (FRET)-based assay. Benserazide was confirmed covalent binder through time-dependent inhibition kinetic analysis, its binding mode elucidated by molecular docking. Notably, exifone not only inhibited but also blocked interaction between host cell receptor angiotensin-converting enzyme (ACE2) spike protein domain (S-RBD), surface plasmon (SPR) flow cytometry. Additionally, demonstrated antiviral various SARS-CoV-2-S pseudovirus variants. In conclusion, discovery underscores in developing conserved for coronaviruses, offering new strategies rapid drugs both current future pandemics.

Язык: Английский

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Potent antiviral activity of simnotrelvir against key epidemic SARS-CoV-2 variants with a high resistance barrier

Antimicrobial Agents and Chemotherapy, Год журнала: 2025, Номер unknown

Опубликована: Март 10, 2025

ABSTRACT Simnotrelvir is an oral small-molecule antiviral agent targeting the 3C-like protease (3CL pro ) of SARS-CoV-2, proven effective against Delta variant with favorable pharmacokinetics and safety in preclinical study. In this study, we further evaluated efficacy simnotrelvir a range emerging Omicron variants, including BA.1, BA.4, BA.5, CH.1.1, XBB.1.5, XBB.1.16, EG.5, JN.1. vitro assays Vero E6 cells confirmed that exhibited robust activity across these comparable to Food Drug Administration (FDA)-approved drug nirmatrelvir. Additionally, demonstrated inhibition several nirmatrelvir-resistant SARS-CoV-2 3CL mutants, A260V, Y54A, (T21I + S144A), F140A, H172Y, E166V. Importantly, showed better potency E166V mutation compared Resistance selection studies revealed BA.5 developed reduced sensitivity after 5 10 passages, increasing IC 50 values by 3.2 4.5-fold, respectively, while HCoV-OC43 8.3-fold increase 12 passages. Despite this, simnotrelvir’s overall remains strong. Furthermore, clinical trials combining ritonavir significantly shortened symptom resolution COVID-19 patients. Genomic analysis treated patients found random nucleotide substitutions but no significant mutations linked resistance. conclusion, shows strong variants maintains high barrier resistance, reinforcing its potential as therapeutic option for current future variants.

Язык: Английский

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