Abstract
The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells requires binding of the viral spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor, which triggers subsequent conformational changes to facilitate viral and cellular fusion at the plasma membrane or following endocytosis. Here, we experimentally identified selective and broad inhibitors of SARS-CoV-2 entry that share a tricyclic ring (or similar) structure. The inhibitory effect was restricted to early steps during infection and the entry inhibitors interacted with the receptor binding domain of the SARS-CoV-2 spike but did not significantly interfere with receptor (ACE2) binding. Instead, some of these compounds induced conformational changes or affected spike assembly and blocked SARS-CoV-2 spike cell-cell fusion activity. The broad inhibitors define a highly conserved binding pocket that is present on the spikes of SARS-CoV-1, SARS-CoV-2, and all circulating SARS-CoV-2 variants tested and block SARS-CoV spike activity required for mediating viral entry. These compounds provide new insights into the SARS-CoV-2 spike topography, as well as into critical steps on the entry pathway, and can serve as lead candidates for the development of broad-range entry inhibitors against SARS-CoVs.
Keywords: SARS-CoV-2; entry inhibitors; mode of action; small molecules; spike.
【저자키워드】 SARS-CoV-2, mode of action, Small molecules, entry inhibitors, Spike., 【초록키워드】 ACE2, coronavirus, spike, SARS-CoV, Infection, SARS-CoV-1, angiotensin-converting enzyme 2, viral entry, Receptor binding domain, glycoprotein, receptor, cell-cell fusion, Critical, binding, SARS-CoV-2 spike, Entry inhibitor, cellular, conformational change, Trigger, host cell, acute respiratory syndrome, SARS-CoV-2 entry, Compound, inhibitory effect, candidate, entry pathway, binding pocket, viral spike, plasma membrane, selective, tested, blocked, affected, conserved, significantly, subsequent, required, facilitate, these compound, interfere, broad inhibitor, circulating SARS-CoV-2 variant, the SARS-CoV-2, 【제목키워드】 spike, function, block, Ring, Tricyclic,