2. Academic Validation
  3. Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CLpro Inhibitors as anti-SARS-CoV-2 Drug Candidate

Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CLpro Inhibitors as anti-SARS-CoV-2 Drug Candidate

  • J Med Chem. 2024 Aug 8;67(15):12760-12783. doi: 10.1021/acs.jmedchem.4c00739.
Zhidong Jiang 1 2 3,  Bo Feng 2 3 4,  Lu Chen 5 6,  Tianqing Nie 1 7,  Shizhao Chen 8,  Li Wang 2 3 9,  Hui Liu 2 3 10,  Ting Yu 2 3,  Yumin Zhang 6,  Miao Zheng 2 3 4,  Yechun Xu 7 3 9,  Hong Liu 2 3,  Yi Zang 1,  Haixia Su 7 3,  Leike Zhang 6 11,  Jia Li 2 3 4 8 9 12,  Yu Zhou 1 2 3 4 9
Affiliations

Affiliations

  • 1 Lingang Laboratory, Shanghai 200031, China.
  • 2 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 5 College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang, Hubei 443002, China.
  • 6 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 8 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 9 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 10 Pharmaceutical College of Henan University, Kaifeng 475004, China.
  • 11 Hubei Jiangxia Laboratory, Wuhan 430200, China.
  • 12 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 39072488 DOI: 10.1021/acs.jmedchem.4c00739
Abstract

SARS-CoV-2 has still been threatening global public health with its emerging variants. Our previous work reported lead compound JZD-07 that displayed good 3CLpro inhibitory activity. Here, an in-depth structural optimization for JZD-07 was launched to obtain more desirable drug candidates for the therapy of SARS-CoV-2 Infection, in which 54 novel derivatives were designed and synthesized by a structure-based drug design strategy. Among them, 24 compounds show significantly enhanced 3CLpro inhibitory potencies with IC50 values less than 100 nM, and 11 compounds dose-dependently inhibit the replication of the SARS-CoV-2 delta variant. In particular, compound 49 has the most desirable Antiviral activity with EC50 of 0.272 ± 0.013 μM against the delta variant, which was more than 20 times stronger than JZD-07. Oral administration of 49 could significantly reduce the lung viral copies of mice, exhibiting a more favorable therapeutic potential. Overall, this investigation presents a promising drug candidate for further development to treat SARS-CoV-2 Infection.

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