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We previously identified a peptide\u2010based pan\u2010CoV fusion inhibitor, termed as EK1, able to bind the HR1 region in viral spike (S) protein S2 subunit. This effectively blocked formation of the six\u2010helix bundle (6\u2010HB)\u00a0fusion core and, thus, showed efficacy against all human coronaviruses (HCoVs).\u00a0EK1\u00a0is now in phase 3 clinical trials. However, the peptide drug generally lacks oral availability. Therefore, we herein performed a structure\u2010based virtual screening of the libraries of biologically active molecules and identified nine candidate compounds. One is Navitoclax, an orally active anticancer drug by inhibition of Bcl\u20102. Like EK1 peptide, it could bind HR1 and block 6\u2010HB\u00a0formation, efficiently inhibiting fusion and infection of all SARS\u2010CoV\u20102\u00a0variants tested, as well as SARS\u2010CoV and MERS\u2010CoV,\u00a0with IC<jats:sub>50<\/jats:sub> values ranging from 0.5 to 3.7\u2009\u03bcM. These findings suggest that Navitoclax is a promising repurposed drug candidate for development as a safe and orally available broad\u2010spectrum antiviral drug to combat the current SARS\u2010CoV\u20102\u00a0and its variants, as well as other HCoVs.<\/jats:p>","DOI":"10.1002\/jmv.29145","type":"journal-article","created":{"date-parts":[[2023,10,8]],"date-time":"2023-10-08T18:45:57Z","timestamp":1696790757000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Repurposing Navitoclax to block SARS\u2010CoV\u20102 fusion and entry by targeting heptapeptide repeat sequence 1 in S2 protein"],"prefix":"10.1002","volume":"95","author":[{"given":"Fanke","family":"Jiao","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and 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