<br>基于结构的针对宿主组织蛋白酶 L 和 calpain-1 的泛冠状病毒抑制剂的设计,Signal Transduction and Targeted Therapy

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基于结构的针对宿主组织蛋白酶 L 和 calpain-1 的泛冠状病毒抑制剂的设计
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2024-03-06 , DOI: 10.1038/s41392-024-01758-8
Xiong Xie _{1,

2} , Qiaoshuai Lan ₃ , Jinyi Zhao _{2,

4} , Sulin Zhang _{1,

2} , Lu Liu _{1,

2,

4} , Yumin Zhang ₅ , Wei Xu ₃ , Maolin Shao _{2,

4} , Jingjing Peng _{1,

2} , Shuai Xia ₃ , Yan Zhu ₄ , Keke Zhang _{1,

6} , Xianglei Zhang ₄ , Ruxue Zhang _{2,

5} , Jian Li _{1,

6} , Wenhao Dai _{1,

2} , Zhen Ge ₆ , Shulei Hu ₁ , Changyue Yu _{1,

2} , Jiang Wang _{1,

2} , Dakota Ma ₁ , Mingyue Zheng _{1,

2,

6,

7} , Haitao Yang ₄ , Gengfu Xiao _{2,

5} , Zihe Rao ₄ , Lu Lu ₃ , Leike Zhang _{2,

5} , Fang Bai ₄ , Yao Zhao ₈ , Shibo Jiang ₃ , Hong Liu _{1,

2,

4,

6,

7}

Affiliation

Drug Discovery and Design Center, State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, 200032, China.
Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Road, Jiangsu, 210023, Nanjing, China.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China.
National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, 518112, China.

由冠状病毒感染引起的呼吸道疾病仍然是全球健康危机。尽管有几种 SARS-CoV-2 特异性疫苗和直接作用抗病毒药物可供使用，但它们对未来新出现的冠状病毒（包括 SARS-CoV-2 变种）的功效可能会受到影响。针对宿主的抗病毒药物提供了预防和治疗策略，以克服耐药性并管理新出现的冠状病毒的未来爆发。组织蛋白酶 L (CTSL) 和钙蛋白酶-1 (CAPN1) 是宿主半胱氨酸蛋白酶，在冠状病毒进入细胞和感染相关免疫反应中发挥着至关重要的作用。在这里，两种拟肽 α-酮酰胺化合物14a和14b被确定为针对 CTSL 和 CAPN1 的有效双靶点抑制剂。人CTSL和CAPN1与14a和14b复合物的X射线晶体结构揭示了14a和14b的α-酮酰胺基团与CTSL的C25和CAPN1的C115共价结合。两者均在体外表现出强效、广谱的抗冠状病毒活性，值得注意的是，它们对 SARS-CoV-2 及其相关变体 (VOC) 表现出低纳摩尔效力，在各种细胞中 EC ₅₀值范围为 0.80 至 161.7 nM 。初步的机制探索表明，它们通过阻止病毒进入而表现出抗冠状病毒活性。此外， 14a和14b在小鼠、大鼠和狗中表现出良好的口服药代动力学特性，并且在小鼠中具有良好的安全性。此外，在 K18-hACE2 转基因小鼠模型中， 14a和14b治疗均显示出针对 SARS-CoV-2 XBB 1.16 变异感染的有效抗病毒效力。 14b还在小鼠模型中表现出针对HCoV-OC43感染的有效抗病毒活性，最终存活率为60%。进一步评估表明， 14a和14b在Raw 264.7小鼠巨噬细胞和急性肺炎小鼠中表现出优异的抗炎作用。总而言之，这些结果表明14a和14b是有前途的候选药物，为开发具有抗病毒和抗炎特性的泛冠状病毒抑制剂提供了新的见解。

"点击查看英文标题和摘要"

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

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 EC₅₀ 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 antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

更新日期：2024-03-06

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