Modulating functional allostery of the host-cell receptor protein hACE2 to inhibit viral entry of SARS-CoV-2

Abstract

The emergence of new SARS-CoV-2 Omicron sub-variants with faster transmission has necessitated accelerated scientific efforts to confront a possible health emergency. Conventional anti-CoV strategies targeting viral proteins often fail due to frequent mutations. Thus, targeting the conserved host receptor angiotensin-converting enzyme 2 (hACE2), which mediates viral entry via interaction with the spike protein's receptor-binding domain (RBD), presents a rational therapeutic alternative. This, however, requires identification of non-orthosteric hACE2 sites and suitable modulators that retain hACE2's physiological function. Using blind docking and unbiased molecular dynamics (MD) simulations, we identify a novel allosteric site on hACE2, distant from its peptidase domain. Simulations show that an allosteric modulator can disrupt hACE2–RBD interaction by perturbing the spike RBD while stabilizing hACE2's binding to its natural substrate, angiotensin II (AngII). Pharmacophore modeling and high-throughput virtual screening (HTVS) of large databases yield more effective modulators. These allosteric binders downregulate hACE2–RBD interaction across three SARS-CoV-2 variants of concern (Beta, Delta, and Omicron). Dynamic residue network analysis reveals the shortest suboptimal pathway through which the allosteric signal is transmitted to the RBD. We believe that the identified site and mechanistic insight offer a promising basis for developing variant-agnostic SARS-CoV-2 therapeutics.