Repurposing Drugs and Synergistic Combinations as Potential Therapies for Inhibiting SARS-CoV-2 and Coronavirus Replication

IF 4.9 Q1 CHEMISTRY, MEDICINAL ACS Pharmacology and Translational Science Pub Date : 2024-11-05 DOI:10.1021/acsptsci.4c0051210.1021/acsptsci.4c00512

Richard Boulon*, Clément Mazeaud, Majid D. Farahani, Mathilde Broquière, Mustapha Iddir, Tania Charpentier, Anaïs Anton, Yann Ayotte, Simon Woo, Alain Lamarre*, Laurent Chatel-Chaix and Steven R. LaPlante*,

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Abstract

Drug repurposing can serve an important role in rapidly discovering medicament options for emerging microbial pandemics. In this study, a pragmatic approach is demonstrated for screening and testing drug combinations as potential broad-spectrum therapies against SARS-CoV-2 and other betacoronaviruses. Rapid cell-based phenotypic small molecule screens were executed using related common-cold-causing HCoV-OC43 betacoronavirus to identify replication inhibitors from a library of drugs approved by regulatory agencies for other indications. Given the best inhibitors, an expedient checkerboard strategy then served to identify synergistic drug combinations. These combinations were then validated using more challenging assays involving SARS-CoV-2 and variants. Promising drug combinations against multiple viral variants were discovered and involved Tilorone with Nelfinavir or Molnupiravir.

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重新利用药物和协同组合作为抑制SARS-CoV-2和冠状病毒复制的潜在疗法

药物再利用可以在快速发现针对新出现的微生物大流行的药物选择方面发挥重要作用。在本研究中，展示了一种实用的方法，用于筛选和测试药物组合，作为针对SARS-CoV-2和其他β -冠状病毒的潜在广谱疗法。使用相关的引起普通感冒的HCoV-OC43倍冠状病毒进行基于细胞的快速表型小分子筛选，从监管机构批准用于其他适应症的药物文库中鉴定复制抑制剂。给定最好的抑制剂，一个权宜之计棋盘策略，然后用于确定协同药物组合。然后使用涉及SARS-CoV-2及其变体的更具挑战性的分析对这些组合进行验证。发现了针对多种病毒变体的有希望的药物组合，包括替洛酮与奈非那韦或莫努匹拉韦。

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来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

期刊介绍： ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.