期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 4, 页码 2956-2970出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01494
关键词
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资金
- National Health and Medical Research Council of Australia [APP1174941]
- Fogarty International Center (FIC) through the International Cooperative Biodiversity Group (ICBG) program [U01 TW006634]
The study identifies cathepsin L as a key protease used by coronaviruses for cell entry and a potential drug target for antiviral treatment against SARS-CoV-2. The researchers discovered that gallinamide A and synthetic analogues are potent inhibitors of cathepsin L, showing promising antiviral activity against SARS-CoV-2. The combination with a TMPRSS2 inhibitor further enhances the antiviral effect.
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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