A Dual-Target-Based Screening Strategy for Anti-SARS-CoV-2 Active Compounds Enabling the Identification of Macrocyclic Peptide Natural Products: Chloropeptins.

IF 3.6 2区生物学 Q2 CHEMISTRY, MEDICINAL

Journal of Natural Products Pub Date : 2025-09-25 DOI:10.1021/acs.jnatprod.5c00634

Aoi Kimishima, Terumasa Ikeda, Otowa Takahashi, Kamrun Naher, Chiduru Watanabe, Reiko Takai-Todaka, Kei Haga, Sota Honma, Yukiko Ujie, Takayuki Uematsu, Masako Honsho, Toshiaki Sunazuka, Teruki Honma, Kazuhiko Katayama, Yukihiro Asami

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引用次数: 0

Abstract

Toward the development of innovative antiviral drugs, potential dual inhibitors were screened from the O̅mura natural compound library by the use of SARS-CoV-2 3CL^pro enzyme activity and SARS-CoV-2 spike trimer-ACE2 ELISA assays. This screening identified macrocyclic peptide natural products, chloropeptins, as potential dual inhibitors. Further evaluation of their anti-SARS-CoV-2 activity against several variants demonstrated their strong potency (IC₅₀ = 2.96-4.36 μM). Pseudovirus and BlaM-Vpr assays utilizing SARS-CoV-2 spike pseudovirus confirmed that chloropeptin 1 effectively blocks viral entry. Additionally, molecular docking simulations revealed that chloropeptins form hydrogen bonds and van der Waals interactions with Lys353 and His34 of ACE2, implicating key roles involved in SARS-CoV-2 spike protein binding. These findings highlight chloropeptins as promising candidates for the development of novel anti-SARS-CoV-2 therapeutics.

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基于双靶点的抗sars - cov -2活性化合物筛选策略，可鉴定大环肽天然产物：氯霉素。

为了开发创新的抗病毒药物，利用SARS-CoV-2 3CLpro酶活性和SARS-CoV-2刺突三聚体ace2酶联免疫吸附试验从O - mura天然化合物文库中筛选出潜在的双重抑制剂。筛选确定了大环肽天然产物，氯肽类，作为潜在的双重抑制剂。进一步的抗sars - cov -2活性评估表明，它们具有很强的效力（IC50 = 2.96-4.36 μM）。利用SARS-CoV-2刺突假病毒进行的假病毒和BlaM-Vpr试验证实，chloropeptin 1有效阻断病毒进入。此外，分子对接模拟显示，chloropeptin与ACE2的Lys353和His34形成氢键和范德华相互作用，暗示了参与SARS-CoV-2刺突蛋白结合的关键作用。这些发现强调了氯霉素是开发新型抗sars - cov -2疗法的有希望的候选者。

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来源期刊

Journal of Natural Products 生物-药学

CiteScore

9.10

自引率

5.90%

发文量

294

审稿时长

2.3 months

期刊介绍： The Journal of Natural Products invites and publishes papers that make substantial and scholarly contributions to the area of natural products research. Contributions may relate to the chemistry and/or biochemistry of naturally occurring compounds or the biology of living systems from which they are obtained. Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin. When new compounds are reported, manuscripts describing their biological activity are much preferred. Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.