Abstract:

Early vaccine development for coronavirus disease 2019 (COVID-19) was possible thanks to the prior knowledge that the main immunogenic protein of coronaviruses is the spike protein. Indeed, once the spike sequence of the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant was determined, vaccines could be developed quickly. In parallel, if virus-host protein-protein interactions (PPIs) are mapped for newly emerging or re-emerging pathogens, key interacting domains can be predicted, and validation of such interactions can help deliver small-molecule inhibitors in a relatively short period of time. Here, we propose a comprehensive pipeline to systematically identify broad-spectrum antivirals in a time-effective manner and complement traditional therapeutic strategies to fight viral infections. Following initial sequencing and virus-host interactome mapping, ultra-large virtual drug screening is conducted on the predicted interacting domains to quickly identify primary hits. The virtual hits and analogs are then experimentally verified using biophysical and biological assays, as well as structural biology techniques. This widely applicable pipeline should allow faster identification of broad-spectrum hits and leads for antiviral drug discovery.