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

Autor: Ashhurst AS; School of Chemistry, The University of Sydney, Sydney, NSW2006, Australia.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW2006, Australia., Tang AH; School of Chemistry, The University of Sydney, Sydney, NSW2006, Australia., Fajtová P; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States.; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610Prague, Czech Republic., Yoon MC; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States., Aggarwal A; Kirby Institute, University of New South Wales, Sydney, NSW2052, Australia., Bedding MJ; School of Chemistry, The University of Sydney, Sydney, NSW2006, Australia., Stoye A; School of Chemistry, The University of Sydney, Sydney, NSW2006, Australia., Beretta L; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States., Pwee D; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States., Drelich A; Department of Microbiology and Immunology, University of Texas, Medical Branch, 3000 University Boulevard, Galveston, Texas77755-1001, United States., Skinner D; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States., Li L; Department of Biochemistry and Biophysics, Texas A&M University, 301 Old Main Drive, College Station, Texas77843, United States., Meek TD; Department of Biochemistry and Biophysics, Texas A&M University, 301 Old Main Drive, College Station, Texas77843, United States., McKerrow JH; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States., Hook V; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States., Tseng CT; Department of Microbiology and Immunology, University of Texas, Medical Branch, 3000 University Boulevard, Galveston, Texas77755-1001, United States., Larance M; Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW2006, Australia., Turville S; Kirby Institute, University of New South Wales, Sydney, NSW2052, Australia., Gerwick WH; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States.; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California92093, United States., O'Donoghue AJ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California92093, United States., Payne RJ; School of Chemistry, The University of Sydney, Sydney, NSW2006, Australia.; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW2006, Australia.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Feb 24; Vol. 65 (4), pp. 2956-2970. Date of Electronic Publication: 2021 Nov 03.
DOI: 10.1021/acs.jmedchem.1c01494
Abstrakt: 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 IC 50 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 EC 50 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.
Databáze: MEDLINE