Engineering an ACE2-Derived Fragment as a Decoy for Novel SARS-CoV-2 Virus

Entry inhibitors are an important resource in the responseagainstemerging pathogens like the novel SARS-CoV-2, which enters human cellsvia interaction between the surface spike glycoprotein and the cellularmembrane receptor angiotensin-converting enzyme 2 (ACE2). Using acombination of comparative structural analyses of the binding surfaceof the spike to ACE2, docking experiments, and molecular dynamicssimulations, we identified a stable fragment of ACE2 that binds tothe spike, is soluble, and is not predicted to bind to its physiologicalligand angiotensin II. From this fragment we computationally designedand experimentally validated a smaller, stable peptide that disruptsACE2-spike interaction at nanomolar concentrations, suggesting itspotential use as a decoy that could interfere with viral binding bycompetition.