2. Academic Validation
  3. Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L

Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L

  • J Med Chem. 2022 Feb 24;65(4):2956-2970. doi: 10.1021/acs.jmedchem.1c01494.
Anneliese S Ashhurst 1 2,  Arthur H Tang 1,  Pavla Fajtová 3 4,  Michael C Yoon 3,  Anupriya Aggarwal 5,  Max J Bedding 1,  Alexander Stoye 1,  Laura Beretta 3,  Dustin Pwee 3,  Aleksandra Drelich 6,  Danielle Skinner 3,  Linfeng Li 7,  Thomas D Meek 7,  James H McKerrow 3,  Vivian Hook 3,  Chien-Te Tseng 6,  Mark Larance 8,  Stuart Turville 5,  William H Gerwick 3 9,  Anthony J O'Donoghue 3,  Richard J Payne 1 10
Affiliations

Affiliations

  • 1 School of Chemistry, The University of Sydney, Sydney, NSW2006, Australia.
  • 2 School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW2006, Australia.
  • 3 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States.
  • 4 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610Prague, Czech Republic.
  • 5 Kirby Institute, University of New South Wales, Sydney, NSW2052, Australia.
  • 6 Department of Microbiology and Immunology, University of Texas, Medical Branch, 3000 University Boulevard, Galveston, Texas77755-1001, United States.
  • 7 Department of Biochemistry and Biophysics, Texas A&M University, 301 Old Main Drive, College Station, Texas77843, United States.
  • 8 Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW2006, Australia.
  • 9 Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California92093, United States.
  • 10 Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW2006, Australia.
PMID: 34730959 DOI: 10.1021/acs.jmedchem.1c01494
Abstract

Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is a promising drug target for novel antivirals against SARS-CoV-2. The marine natural product gallinamide A and several synthetic analogues were identified as potent inhibitors of Cathepsin L with IC50 values in the picomolar range. Lead molecules possessed selectivity over Other cathepsins and alternative host proteases involved in viral entry. Gallinamide A directly interacted with Cathepsin L in cells and, together with two lead analogues, potently inhibited SARS-CoV-2 Infection in vitro, with EC50 values in the nanomolar range. Reduced Antiviral activity was observed in cells overexpressing transmembrane protease, serine 2 (TMPRSS2); however, a synergistic improvement in Antiviral activity was achieved when combined with a TMPRSS2 inhibitor. These data highlight the potential of Cathepsin L as a COVID-19 drug target as well as the likely need to inhibit multiple routes of viral entry to achieve efficacy.

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