相同与不相同：口服治疗COVID-19的第二代非肽共价3CL蛋白酶抑制剂S-892216的发现

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-10-09 DOI:10.1021/acs.jmedchem.5c02784

Shaun R Stauffer

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引用次数: 0

摘要

COVID-19大流行凸显了对有效抗病毒治疗的迫切需要。虽然疫苗在减轻疾病严重程度方面发挥了重要作用，但变体和长时间covid症状的出现凸显了抗病毒治疗干预措施的持续重要性。以3CLpro为主蛋白酶为靶点的临床药物鉴定已取得成功；然而，现有的选择有限，并且仍需要改进以获得更广泛的临床应用。利用已建立的中心支架开发ensitrelvir，利用结构知识利用非共价和共价作用模式确定S-892216为潜在的同类最佳可逆性共价非肽3CLpro抑制剂，具有卓越的临床前特征，可用于治疗COVID-19和未来的大流行防范。

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The Same and Not the Same: Discovery of S-892216, A Second-Generation Nonpeptidic Covalent 3CL Protease Inhibitor for Oral COVID-19 Therapeutics.

The COVID-19 pandemic underscored the critical need for effective antiviral therapeutics. While vaccines have been instrumental in mitigating disease severity, the emergence of variants and long-COVID symptoms highlight the ongoing importance of antiviral therapeutic interventions. Targeting the 3CLpro main protease has been successful in identifying clinical agents; however limited options exist, and improvements are still required to have broader clinical utility. Utilizing the established central scaffold to develop ensitrelvir, both noncovalent and covalent modes of action were leveraged using structural knowledge to identify S-892216 as a potential best-in-class reversible covalent nonpeptidic 3CLpro inhibitor with a superior preclinical profile for treatment of COVID-19 and future pandemic preparedness.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.