The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses. Small molecule drugs promise to remain a valuable tool in controlling the ongoing COVID-19 pandemic. Here the authors describe optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for potential treatment of COVID-19.
【저자키워드】 Small molecules, Proteases, Lead optimization, 【초록키워드】 COVID-19, Treatment, Structure, SARS-CoV-2, Coronaviruses, coronavirus, therapy, SARS-COV-2 infection, COVID-19 pandemic, drug, protease, Replication, Protease inhibitor, specificity, stability, Pandemics, drug target, small molecule, in vivo, Critical, SARS-CoV-2 replication, 3CL, binding, cellular, pharmacokinetic, Potential treatment, maturation, complex, Compound, human cells, binding pocket, these compounds, antiviral potency, selected, characterized, inhibiting, eliminating, inhibit SARS-CoV-2, small molecule inhibitor, the SARS-CoV-2, 【제목키워드】 COVID-19, Treatment, protease, development, 3CL, small molecule inhibitor, the SARS-CoV-2,