A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease

  • J Med Chem. 2023 Aug 24;66(16):11040-11055. doi: 10.1021/acs.jmedchem.3c00221.
Zhi Zachary Geng  1 ,  Sandeep Atla  1 ,  Namir Shaabani  2 ,  Veerabhadra Vulupala  1 ,  Kai S Yang  1 ,  Yugendar R Alugubelli  1 ,  Kaustav Khatua  1 ,  Peng-Hsun Chen  1 ,  Jing Xiao  1 ,  Lauren R Blankenship  1 ,  Xinyu R Ma  1 ,  Erol C Vatansever  1 ,  Chia-Chuan D Cho  1 ,  Yuying Ma  1 ,  Robert Allen  2 ,  Henry Ji  2 ,  Shiqing Xu  1  3 ,  Wenshe Ray Liu  1  4  5  6
Affiliations
  • 1. Department of Chemistry, Texas A&M Drug Discovery Laboratory, Texas A&M University, College Station, Texas 77843, United States.
  • 2. Sorrento Therapeutics, Inc. San Diego, California 92121, United States.
  • 3. Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas 77843, United States.
  • 4. Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
  • 5. Institute of Biosciences and Technology and Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, Texas 77030, United States.
  • 6. Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, Texas 77843, United States.
PMID: 37561993 DOI: 10.1021/acs.jmedchem.3c00221
Abstract

SARS-CoV-2, the COVID-19 pathogen, relies on its main protease (MPro) for replication and pathogenesis. MPro is a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as MPro inhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 dipeptidyl MPro inhibitors and characterized them on enzymatic inhibition potency, structures of their complexes with MPro, cellular MPro inhibition potency, Antiviral potency, cytotoxicity, and in vitro metabolic stability. Our results indicated that MPro has a flexible S2 pocket to accommodate inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as (S)-2-azaspiro [4,4]nonane-3-carboxylate and (S)-2-azaspiro[4,5]decane-3-carboxylate have favorable characteristics. One compound, MPI60, containing a P2 (S)-2-azaspiro[4,4]nonane-3-carboxylate displayed high Antiviral potency, low cellular cytotoxicity, and high in vitro metabolic stability.