Targeting ACE2-RBD Interaction as a Platform for COVID-19 Therapeutics: Development and Drug-Repurposing Screen of an AlphaLISA Proximity Assay

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, is a pressing public health emergency garnering a rapid response from scientists across the globe. Host cell invasion is initiated through direct binding of the viral spike protein to the host receptor angiotensin-converting enzyme 2 (ACE2). Disrupting the spike protein-ACE2 interaction is a potential therapeutic target for treating COVID-19. We have developed a proximity-based AlphaLISA assay to measure the binding of SARS-CoV-2 spike protein receptor binding domain (RBD) to ACE2. Utilizing this assay platform, a drug-repurposing screen against 3384 small-molecule drugs and preclinical compounds was carried out, yielding 25 high-quality primary hits, of which only corilagin was validated in cherry-picking. This established AlphaLISA RBD-ACE2 platform can facilitate evaluation of biologics or small molecules that can perturb this essential viral-host interaction to further the development of interventions to address the global health pandemic.