We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC 50 : 13 nM), SARS-CoV-2 (IC 50 : 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC 50 : 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC 100 ) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR) analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike protein trimer. These small-molecule inhibitors prevented virus-mediated cell–cell fusion. The absorption, distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in rats demonstrated an excellent half-life (t 1/2 ) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates.
【저자키워드】 COVID-19, SARS-CoV-2, SARS-CoV, MERS-CoV, Severe acute respiratory syndrome (SARS), fusion inhibitor, Middle East respiratory syndrome (MERS), pan-coronavirus, 【초록키워드】 coronavirus, B.1.351, India, variant, variants of concern, B.1.617.2, surface plasmon resonance, delta variant, SPR, inhibitors, metabolism, ADME, B.1.1.7, African, SARS-CoV-2 spike protein, VOCs, small molecule, in vivo, inhibitor, distribution, Cytopathic effect, Analysis, Middle East, Candidates, acute respiratory syndrome, half-maximal inhibitory concentration, Compound, activities, trimer, South, respiratory syndrome coronavirus, prefusion, inhibitory, oral bioavailability, bind, lowest, inhibited, facilitate, demonstrated, prevented, 【제목키워드】 activity, VOCs, concern, fusion, potent, Major, Potential,