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
  • 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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