Abstract
The severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 remains a persistent threat to mankind, especially for the immunocompromised and elderly for which the vaccine may have limited effectiveness. Entry of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus entry into target cells. We report the identification of such inhibitors through a robust high-throughput screen testing 15,000 small molecules from unique libraries. Several leads were validated in a suite of mechanistic assays, including whole cell SARS-CoV-2 infectivity assays. The main lead compound, calpeptin, was further characterized using SARS-CoV-1 and the novel SARS-CoV-2 variant entry assays, SARS-CoV-2 protease assays and molecular docking. This study reveals calpeptin as a potent and specific inhibitor of SARS-CoV-2 and some variants.
Keywords: Anti-viral drugs; HTS; Inhibitor; SARS-CoV-2; Virus entry.
【저자키워드】 SARS-CoV-2, virus entry, inhibitor, Anti-viral drugs, HTS, 【초록키워드】 COVID-19, coronavirus, Mutation, SARS-CoV-2 variant, molecular docking, protease, severe acute respiratory syndrome Coronavirus, SARS-CoV-1, angiotensin-converting enzyme 2, variants, Spike protein, Transmissibility, virus entry, Effectiveness, Immunocompromised, small molecule, novel, inhibitor, Small molecule inhibitors, Anti-viral drugs, Interaction, angiotensin, target cells, specific inhibitor, viral spike protein, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, SARS-CoV-2 protease, high affinity, cellular receptor, variants of SARS-CoV-2, Cell, robust, responsible, assays, characterized, unique, the spike protein, reveal, the vaccine, highlighting, infectivity assays, small molecule inhibitor, 【제목키워드】 identification, SARS-CoV-2 entry, small molecule inhibitor,