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

• Published in: Journal of medicinal chemistry 2022-02, Vol.65 (4), p.2956-2970
• Main Authors: Ashhurst, Anneliese S., Tang, Arthur H., Fajtová, Pavla, Yoon, Michael C., Aggarwal, Anupriya, Bedding, Max J., Stoye, Alexander, Beretta, Laura, Pwee, Dustin, Drelich, Aleksandra, Skinner, Danielle, Li, Linfeng, Meek, Thomas D., McKerrow, James H., Hook, Vivian, Tseng, Chien-Te, Larance, Mark, Turville, Stuart, Gerwick, William H., O’Donoghue, Anthony J., Payne, Richard J.
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Antimicrobial Cationic Peptides - chemical synthesis; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - pharmacology; Cathepsin L - antagonists & inhibitors; Cathepsin L - metabolism; Chlorocebus aethiops; COVID-19 - metabolism; COVID-19 Drug Treatment; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular Conformation; Proteomics; SARS-CoV-2 - drug effects; Structure-Activity Relationship; Vero Cells
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01494

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.