Discovery of Small-Molecule Orthopoxvirus Resolvase Inhibitors with Antiviral Activity.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-06-19 DOI:10.1021/acs.jmedchem.5c00019

Jacob P Mahoney,Samuel Offei,Anil Pant,Ziyue Wang,Benjamin Weiner,Lulu Yin,Won Hee Ryu,Roshan Katekar,Jessica M Williams,Hideki Aihara,Zhilong Yang,Zhengqiang Wang

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引用次数: 0

Abstract

Poxvirus genome replication and viral maturation require a Holliday junction resolvase. Genetic evidence suggests that targeting the virally encoded resolvase could offer a novel antiviral approach against orthopoxviruses. However, orthopoxvirus resolvases have not been characterized biochemically and pharmacologically, and inhibitors remain unknown. Herein, we have developed and optimized the first in vitro assay directly measuring the activity of mpox virus (MPXV) resolvase (Mpr) and vaccinia virus (VACV) resolvase (A22). The subsequent pilot screen of an in-house compound library using this assay identified multiple inhibitors, each inhibiting both Mpr and A22, and conferring antiviral activity against VACV. Computationally, these inhibitors docked well into the active site of an AlphaFold-generated Mpr structural model. The assay developed herein and the inhibitors identified and characterized provide a valuable platform for developing compounds as broad-spectrum antiviral drug leads against MPXV and other potentially emerging orthopoxviruses, and as probes to investigate the functions of Mpr.

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具有抗病毒活性的小分子正痘病毒分解抑制剂的发现。

痘病毒基因组复制和病毒成熟需要Holliday连接分解。遗传证据表明，以病毒编码的分解酶为靶点可能提供一种新的抗病毒方法来对抗正痘病毒。然而，正痘病毒分解酶还没有生物化学和药理学特征，抑制剂仍然未知。在此，我们建立并优化了第一个直接测定m痘病毒（MPXV）分解瓶（Mpr）和牛痘病毒（VACV）分解瓶（A22）活性的体外检测方法。随后使用该试验对内部化合物文库进行先导筛选，鉴定出多种抑制剂，每种抑制剂均抑制Mpr和A22，并具有抗VACV的抗病毒活性。通过计算，这些抑制剂很好地与alphafold生成的Mpr结构模型的活性位点对接。本文所建立的实验以及所鉴定和表征的抑制剂为开发针对MPXV和其他可能出现的正痘病毒的广谱抗病毒药物先导化合物以及研究Mpr功能的探针提供了有价值的平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.