X-206 exhibits broad-spectrum anti-β-coronavirus activity, covering SARS-CoV-2 variants and drug-resistant isolates

Jiei Sasaki; Akihiko Sato; Michihito Sasaki; Iori Okabe; Kota Kodama; Satoko Otsuguro; Kosuke Yasuda; Hirotatsu Kojima; Yasuko Orba; Hirofumi Sawa; Katsumi Maenaka; Yusuke Yanagi; Takao Hashiguchi

doi:10.1016/j.antiviral.2024.106039

X-206 exhibits broad-spectrum anti-β-coronavirus activity, covering SARS-CoV-2 variants and drug-resistant isolates

Antiviral Res. 2024 Nov 19:232:106039. doi: 10.1016/j.antiviral.2024.106039. Online ahead of print.

Authors

Jiei Sasaki¹, Akihiko Sato², Michihito Sasaki³, Iori Okabe⁴, Kota Kodama⁵, Satoko Otsuguro⁶, Kosuke Yasuda⁷, Hirotatsu Kojima⁷, Yasuko Orba³, Hirofumi Sawa⁸, Katsumi Maenaka⁹, Yusuke Yanagi⁴, Takao Hashiguchi¹⁰

Affiliations

¹ Laboratory of Medical Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
² Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, Toyonaka, Japan; Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Japan.
³ Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Japan.
⁴ Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
⁵ Medical Data Science Lab., Hoshi University, Tokyo, Japan; Laboratory of Biomolecular Science, and Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
⁶ Laboratory of Biomolecular Science, and Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
⁷ Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
⁸ Institute for Vaccine Research and Development, Hokkaido University, Sapporo, Japan.
⁹ Laboratory of Biomolecular Science, and Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; Division of Pathogen Structure, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Global Station for Biosurfaces and Drug Discovery, Hokkaido University, Sapporo, Japan.
¹⁰ Laboratory of Medical Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan; Kyoto University Immunomonitoring Center, Kyoto University, Kyoto, Japan. Electronic address: hashiguchi.takao.1a@kyoto-u.ac.jp.

PMID: 39571911
DOI: 10.1016/j.antiviral.2024.106039

Abstract

Coronaviruses such as the Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2, causing MERS, SARS, and Coronavirus disease-19, respectively, are highly pathogenic to humans. Notably, several antiviral drugs against SARS-CoV-2, such as nirmatrelvir and remdesivir, have been approved. However, no approved vaccines or antiviral agents are available for other highly pathogenic β-coronaviruses. In this study, we identified two compounds, thapsigargin and X-206, that exhibit antiviral activities against SARS-CoV, MERS-CoV, and SARS-CoV-2. Notably, both compounds effectively inhibited the cell-to-cell fusion mediated by the Spike proteins of all three β-coronaviruses. X-206 exhibited antiviral activity against nirmatrelvir- and remdesivir-resistant SARS-CoV-2 isolates and SARS-CoV-2 variants, including Delta, BA.5, and XBB.1. Consequently, the mechanism of action of these compounds with anti-β-coronavirus activities may differ from that of the approved direct-acting drugs for SARS-CoV-2, thereby offering potential use as a cocktail with other antivirals, and serving as a chemical basis for developing therapeutic agents against β-coronaviruses in preparation for the next spillover and pandemic.

Keywords: Antiviral compound; COVID-19; Coronavirus; MERS; SARS.