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

• Published in: Antiviral research 2024-12, Vol.232, p.106039, Article 106039
• Main Authors: Sasaki, Jiei, Sato, Akihiko, Sasaki, Michihito, Okabe, Iori, Kodama, Kota, Otsuguro, Satoko, Yasuda, Kosuke, Kojima, Hirotatsu, Orba, Yasuko, Sawa, Hirofumi, Maenaka, Katsumi, Yanagi, Yusuke, Hashiguchi, Takao
• Format: Article
• Language: English
• Subjects: Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - pharmacology; Alanine - analogs & derivatives; Alanine - pharmacology; Animals; Antiviral Agents - pharmacology; Antiviral compound; Chlorocebus aethiops; Coronavirus; COVID-19; COVID-19 - virology; COVID-19 Drug Treatment; Drug Resistance, Viral; Humans; MERS; Middle East Respiratory Syndrome Coronavirus - drug effects; SARS; SARS-CoV-2 - drug effects; Severe acute respiratory syndrome-related coronavirus - drug effects; Spike Glycoprotein, Coronavirus - metabolism; Vero Cells; Virus Internalization - drug effects
• ISSN: 0166-3542; 1872-9096; 1872-9096
• DOI: 10.1016/j.antiviral.2024.106039

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. •X-206 is effective against SARS-CoV-2 variants and drug-resistant isolates.•X-206 appears to provide dual inhibition at steps of membrane fusion and post-viral entry.•X-206 can be combined with approved drugs for SARS-CoV-2 antiviral therapy.