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一种针对人类冠状病毒M^pro的新型共价宽谱抑制剂

Jing Sun^1,2, Deheng Sun³, Qi Yang^1,4

¹State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong Province, 510182, China.

Nature communications

|May 15, 2025

概括

一种名为ISM3312的新药通过向主要蛋白酶 (Mpro) 来有效抑制多种人类冠状病毒. 这种广泛的抗病毒药物显示出对抗耐药菌株的前景,提高了对未来病毒威胁的准备.

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:

人类冠状病毒 (CoV) 引起了一系列呼吸系统疾病,由于它们的遗传多样性,这给公共卫生带来了重大挑战.
开发广泛的抗病毒疗法对于管理特有和新出现的COV感染至关重要.
主蛋白酶 (Mpro) 是许多冠状病毒的保存标,为广泛抑制提供了潜在的策略.

研究的目的:

设计和识别针对SARS-CoV-2主要蛋白酶 (Mpro) 的新型小分子非类抑制剂.
评估针对一系列人类冠状病毒的已识别的抑制剂的抗病毒活性和安全概况.

主要方法:

利用生成化学平台Chemistry42进行新的分子设计.
进行了广泛的虚拟选和基于结构的优化,以识别化合物.
评估了对多种人类冠状病毒的抗病毒活性,包括SARS-CoV-2,MERS-CoV和其他常见的CoV.
评估了目标之外的风险和抑制P-糖蛋白 (P-gp).
对耐尼马特里尔维尔耐药的Mpro突变物进行了有效性测试.

主要成果:

确定ISM3312作为一种新的,不可逆转的,共价Mpro抑制剂,具有低的脱风险.
证明ISM3312对SARS-CoV-2,MERS-CoV,229E,OC43,NL63和HKU1的突出的广泛抗病毒活性,独立于P-gp抑制.
展示了ISM3312对耐尼马特里尔病毒耐药的Mpro突变的显著抑制作用.

结论:

ISM3312代表了一个有前途的治疗候选人,用于广泛的冠状病毒抑制.
它对抗耐药菌株的有效性表明它在克服病毒逃生机制方面发挥了作用.
将ISM3312与现有的抗病毒药物结合起来,可以加强对未来的冠状病毒流行病的防御.

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