De novo design of SARS-CoV-2 main protease inhibitors with characteristic binding modes PMID: 38925121

ADC Targets in Oncology

2026-04-10

De novo design of SARS-CoV-2 main protease inhibitors with characteristic binding modes

Structure. 2024 Sep 5;32(9):1327-1334.e3. doi: 10.1016/j.str.2024.05.019.

Yan Zhu ¹ , Jiaolong Meng ² , Bo Feng ³ , Yao Zhao ⁴ , Yi Zang ⁵ , Lingling Lu ² , Mingbo Su ³ , Qi Yang ⁶ , Qi Zhang ⁷ , Lu Feng ⁸ , Jinyi Zhao ⁷ , Maolin Shao ⁹ , Yuanyuan Ma ⁷ , Xiuna Yang ⁷ , Haitao Yang ⁷ , Jia Li ¹⁰ , Xuefeng Jiang ¹¹ , Zihe Rao ¹²

Affiliations

1. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen 518112, China.
2. State Key Laboratory of Molecular & Process Engineering, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
3. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
4. National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen 518112, China. Electronic address: [email protected].
5. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Lingang Laboratory, Shanghai 200031, China.
6. Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China.
7. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
8. State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, Nankai University, and Tianjin Key Laboratory of Protein Sciences, Tianjin 300071, China.
9. Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100091, China.
10. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China. Electronic address: [email protected].
11. State Key Laboratory of Molecular & Process Engineering, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. Electronic address: [email protected].
12. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, Nankai University, and Tianjin Key Laboratory of Protein Sciences, Tianjin 300071, China; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100091, China. Electronic address: [email protected].

Abstract

The coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly all over the world. The main protease (M^pro) is significant to the replication and transcription of viruses, making it an attractive drug target against coronaviruses. Here, we introduce a series of novel inhibitors which are designed de novo through structure-based drug design approach that have great potential to inhibit SARS-CoV-2 M^proin vitro. High-resolution structures show that these inhibitors form covalent bonds with the catalytic cysteine through the novel dibromomethyl ketone (DBMK) as a reactive warhead. At the same time, the designed phenyl group beside the DBMK warhead inserts into the cleft between H41 and C145 through π-π stacking interaction, splitting the catalytic dyad and disrupting proton transfer. This unique binding model provides novel clues for the cysteine protease inhibitor development of SARS-CoV-2 as well as Other pathogens.

Keywords

SARS-CoV-2; coronavirus; drug resistance; inhibitor; main protease.