Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

作者：Xiong Xie, Qiaoshuai Lan, Jinyi Zhao, Sulin Zhang, Lu Liu, Yumin Zhang, Wei Xu, Maolin Shao, Jingjing Peng, Shuai Xia, Yan Zhu, Keke Zhang, Xianglei Zhang, Ruxue Zhang, Jian Li, Wenhao Dai, Zhen Ge, Shulei Hu, Changyue Yu, Jiang Wang, Dakota Ma, Mingyue Zheng, Haitao Yang, Gengfu Xiao, Zihe Rao, Lu Lu, Leike Zhang, Fang Bai, Yao Zhao, Shibo Jiang, Hong Liu · 发表于：Signal Transduction and Targeted Therapy · 年份：2024 · DOI：10.1038/s41392-024-01758-8 · 被引用次数：23 · 研究领域：Calpain Protease Function and Regulation、interferon and immune responses、SARS-CoV-2 and COVID-19 Research

Abstract Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b , were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC 50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antivi...