Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity

  • J Med Chem. 2025 Sep 25;68(18):19339-19376. doi: 10.1021/acs.jmedchem.5c01520.
Philipp Flury  1  2 ,  Jyoti Vishwakarma  3 ,  Katharina Sylvester  4 ,  Nobuyo Higashi-Kuwata  5 ,  Agnieszka K Dabrowska  3 ,  Renee Delgado  3 ,  Ashley Cuell  3 ,  Rahul Basu  3 ,  Alexander B Taylor  3  6 ,  Ellen Gonçalves de Oliveira  7  8 ,  Mateus Sá Magalhães Serafim  7  8 ,  Jingxin Qiao  9 ,  Yan Chen  9 ,  Shengyong Yang  9 ,  Anthony J O'Donoghue  8 ,  Hiroaki Mitsuya  5 ,  Michael Gütschow  4 ,  Stefan A Laufer  1  2 ,  Christa E Müller  4 ,  Reuben S Harris  3  10 ,  Thanigaimalai Pillaiyar  1  2
Affiliations
  • 1. Institute of Pharmaceutical Sciences, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, Germany.
  • 2. Tübingen Center for Academic Drug Discovery & Development (TüCAD2), Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, Germany.
  • 3. Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • 4. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, Germany.
  • 5. Department of Refractory Viral Diseases, National Institute of Global Health and Medicine, Japan Institute for Health Security, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
  • 6. Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • 7. Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
  • 8. Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 9500 Gilman Drive, San Diego, La Jolla, California 92093-0657, United States.
  • 9. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 10. Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, Texas, 78229, United States.
PMID: 40932417 DOI: 10.1021/acs.jmedchem.5c01520
Abstract

Mpro of SARS-CoV-2 plays a vital role in the replication and pathogenesis of virus. Additionally, its high conservation within the Coronaviridae family makes it an attractive therapeutic target for developing broad-spectrum agents. This study describes the design, synthesis, and structure-activity relationships of azapeptide-based SARS-CoV-2 Mpro inhibitors, leading to several compounds with nanomolar IC50 values. Examples include 14r (IC50 = 13.3 nM), 14s (IC50 = 30.6 nM), 20a (TPG-20a, IC50 = 28.0 nM), and 20g (IC50 = 30.4 nM). Some compounds inhibit MERS-CoV and SARS-CoV-1 Mpro but not the human protease Cathepsin L. Several inhibitors, such as 20a and 20f, exhibit Antiviral activity with potencies comparable to nirmatrelvir and activity against the E166V-carrying SARS-CoV-2 variant (SARS-CoV-2E166V). An Mpro cocrystal structure with 20a shows a covalent adduct with the catalytic Cys145. Overall, these new inhibitors are promising chemical tools that may contribute to the identification of future pan-anticoronaviral drugs.

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