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Evaluating Z-FA-FMK, a host cathepsin L protease inhibitor, as a potent and broad-spectrum antiviral therapy against SARS-CoV-2 and related coronaviruses.

Abstract
Even though the World Health Organization announced the end of the COVID-19 pandemic as a global public health emergency on May 5, 2023, SARS-CoV-2 continues to pose a significant health threat worldwide, resulting in substantial numbers of infections and fatalities. This study investigated the antiviral potential of Z-FA-FMK (FMK), a novel host cathepsin L protease inhibitor, against SARS-CoV-2 infection using both in vitro and in vivo models. In vitro assessments of FMK against a diverse set of SARS-CoV-2 strains, including the Wuhan-like strain and nine variants, demonstrated potent inhibition with EC50 values ranging from 0.55 to 2.41 μM, showcasing similar or superior efficacy compared to FDA-approved antivirals nirmatrelvir (NTV) and molnupiravir (MPV). In vivo experiments using orally administered FMK (25 mg/kg) in SARS-CoV-2-infected K18 hACE2 transgenic mice revealed improved survival rates of 60% and accelerated recovery compared to NTV and MPV treatments. Additionally, FMK displayed a longer half-life (17.26 ± 8.89 h) than NTV and MPV in the mouse model. Due to its host-targeting mechanism, FMK offers potential advantages such as reduced drug resistance and broad-spectrum antiviral activity against multiple coronaviruses. These findings indicate that FMK may serve as a promising candidate for further clinical evaluation in the fight against SARS-CoV-2.
AuthorsJu Hwan Jeong, Jang-Hoon Choi, Beom Kyu Kim, Seong Cheol Min, Santosh Chokkakula, Sol Oh, Ji-Hyun Park, Sang-Mu Shim, Eung-Gook Kim, Young Ki Choi, Joo-Yeon Lee, Yun Hee Baek, Min-Suk Song
JournalAntiviral research (Antiviral Res) Vol. 216 Pg. 105669 (08 2023) ISSN: 1872-9096 [Electronic] Netherlands
PMID37437781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2023. Published by Elsevier B.V.
Chemical References
  • Protease Inhibitors
  • MDL 201053
  • Cathepsin L
  • Anti-Infective Agents
  • Antiviral Agents
  • Enzyme Inhibitors
Topics
  • Animals
  • Mice
  • Humans
  • Protease Inhibitors (pharmacology, therapeutic use)
  • SARS-CoV-2
  • Cathepsin L
  • Pandemics
  • COVID-19
  • Anti-Infective Agents
  • Antiviral Agents (pharmacology, therapeutic use)
  • Enzyme Inhibitors

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