2. Academic Validation
  3. Exploration of P1 and P4 modifications of nirmatrelvir: Design, synthesis, biological evaluation, and X-ray structural studies of SARS-CoV-2 Mpro inhibitors

Exploration of P1 and P4 modifications of nirmatrelvir: Design, synthesis, biological evaluation, and X-ray structural studies of SARS-CoV-2 Mpro inhibitors

  • Eur J Med Chem. 2024 Mar 5:267:116132. doi: 10.1016/j.ejmech.2024.116132.
Arun K Ghosh 1,  Monika Yadav 2,  Satyanarayana Iddum 2,  Somayeh Ghazi 2,  Emma K Lendy 3,  Uttara Jayashankar 4,  Sydney N Beechboard 3,  Yuki Takamatsu 5,  Shin-Ichiro Hattori 5,  Masayuki Aamano 6,  Nobuyo Higashi-Kuwata 5,  Hiroaki Mitsuya 7,  Andrew D Mesecar 8
Affiliations

Affiliations

  • 1 Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA. Electronic address: [email protected].
  • 2 Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA.
  • 3 Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA.
  • 4 Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.
  • 5 Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo, 162-8655, Japan.
  • 6 Department of Clinical Retrovirology, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan.
  • 7 Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo, 162-8655, Japan; Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD, 20892, USA.
  • 8 Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA; Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA; Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.
PMID: 38335815 DOI: 10.1016/j.ejmech.2024.116132
Abstract

We report the synthesis, biological evaluation, and X-ray structural studies of a series of SARS-CoV-2 Mpro inhibitors based upon the X-ray crystal structure of nirmatrelvir, an FDA approved drug that targets the main protease of SARS-CoV-2. The studies involved examination of various P4 moieties, P1 five- and six-membered lactam rings to improve potency. In particular, the six-membered P1 lactam ring analogs exhibited high SARS-CoV-2 Mpro inhibitory activity. Several compounds effectively blocked SARS-CoV-2 replication in VeroE6 cells. One of these compounds maintained good Antiviral activity against variants of concern including Delta and Omicron variants. A high-resolution X-ray crystal structure of an inhibitor bound to SARS-CoV-2 Mpro was determined to gain insight into the ligand-binding properties in the Mpro active site.

Keywords

Antiviral; COVID-19; Protease inhibitor; SARS-CoV-2 mpro; Synthesis; X-ray structure.

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