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针对性选和合理优化bazedoxifene类似物作为泛变体SARS-CoV-2进入抑制剂,改善药理动力学

Binita Patra¹, Nirmal Das¹, Akshay Joshi²

¹Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, WB, India.

European journal of medicinal chemistry

|December 25, 2025

概括

作为一种SERM药物,巴兹西芬通过破坏尖端蛋白结合,意外地抑制了SARS-CoV-2的进入. 一种经过修改的模拟物,化合物74,显示出增强的功效和改善的药理动力学特性,使其成为新抗病毒药物的有希望的领先物.

科学领域:

病毒学病毒学
药物发现药物发现药物发现
药用化学医学化学

背景情况:

SARS-CoV-2的进入依赖于尖蛋白与ACE2受体的结合.
现有的抗病毒药物面临着新兴变种和耐药性的挑战.
美国食品和药物管理局批准的药物提供了一个潜在的来源,用于对抗病毒感染.

研究的目的:

为了确定FDA批准的抑制SARS-CoV-2进入的药物.
描述已识别的化合物的抗病毒活性和机制.
开发具有增强功效和药理动力学特征的改进类型.

主要方法:

使用尖峰RBD-ACE2相互作用试验对FDA批准的药物的查.
在实验室测试中使用伪病毒和活SARS-CoV-2菌株,包括变种.
结构-活性关系 (SAR) 研究和化学修饰.
化合物的药理动力学 (PK) 参数分析.

主要成果:

鉴定出bazedoxifene是一种强大的SARS-CoV-2进入抑制剂,对多种变种和Khosta-2有效.
机理学研究证实了bazedoxifene在进入阶段的作用.
化合物74是一种C5修饰的模拟物,表现出优异的活病毒抑制 (IC50=0.45μM) 和改善的PK特性.
在C5的代谢稳定被确定为增强类药物特性的关键.

结论:

巴兹西芬是一种有前途的进入抑制剂,具有广泛的潜力.
化合物74代表了一种代谢稳定和强大的下一代抗病毒.
用SERM衍生化合物向病毒进入提供了一个可行的治疗策略.

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