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
  • 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.