De Novo Discovery of a Noncovalent Cell-Penetrating Bicyclic Peptide Inhibitor Targeting SARS-CoV-2 Main Protease

  • J Med Chem. 2024 Nov 28;67(22):20258-20274. doi: 10.1021/acs.jmedchem.4c01639.
Yahong Tan  1 ,  Jinyue Yang  2  3 ,  Min Wang  3 ,  Qi Peng  3 ,  Yongqi Li  3 ,  Lifeng Fu  3 ,  Mengmeng Zhang  1 ,  Jiang Wu  4  5 ,  Guanya Yang  4  5 ,  Christopher John Hipolito  6 ,  Youming Zhang  1 ,  Jianxun Qi  3 ,  Yi Shi  3  7  8 ,  Yizhen Yin  1  9
Affiliations
  • 1. State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China.
  • 2. College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
  • 3. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 4. AI and Life Sciences Institute (Hong Kong) Limited, 6/F., Building 17W, No. 17 Science Park West Avenue, Hong Kong Science Park, Pak Shek Kok, New Territories, Hong Kong.
  • 5. Laboratory for Synthetic Chemistry and Chemical Biology Limited, Units 1503-1511, 15/F., Building 17W, Hong Kong Science Park, Shatin 999077, Hong Kong.
  • 6. Screening & Compound Profiling, Quantitative Biosciences, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • 7. Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 8. Beijing Life Science Academy, Beijing 102209, China.
  • 9. Shandong Research Institute of Industrial Technology, Jinan 250101, China.
PMID: 39552553 DOI: 10.1021/acs.jmedchem.4c01639
Abstract

Macrocyclic peptides have garnered significant attention as promising drug candidates. However, they typically face challenges in achieving and enhancing cell permeability for access to intracellular targets. In this study, we focused on the de novo screening of macrocyclic peptide inhibitors against the main protease (Mpro) of SARS-CoV-2 and identified novel noncovalently bound macrocyclic peptides that effectively inhibit proteolytic activity. High-resolution crystal structures further revealed molecular interactions between the macrocyclic peptides and Mpro. Subsequently, a specific macrocyclic peptide lacking cell permeability was further optimized and transformed into a low-toxicity, metabolically stable bicyclic peptide with a cell penetration capacity and therapeutic potential against SARS-CoV-2. The bicyclic peptide was achieved using a novel strategy that involved introducing both a bicyclic structure and a bridging perfluorobiphenyl group. Our study not only provides a lead peptide inhibitor for COVID-19 but also offers valuable insights into achieving cell penetration for macrocyclic peptides through strategic modifications.

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