Deadbolt Drug Discovery: Locking the Door to Class 1 Viral Entry by Small Molecules

The continued emergence of viral pathogens underscores the need for novel antiviral therapeutics with improved efficacy. Small-molecule inhibitors of viral entry are attractive antiviral agents because they block the virus at its earliest step, preventing the virus from entering host cells and causing downstream damage. Some of the viruses of greatest concern for human health, such as human immunodeficiency virus, respiratory syncytial virus, influenza virus, Ebola virus, severe acute respiratory syndrome coronavirus 2, and Lassa virus, encode Class 1 fusion proteins which mediate membrane fusion and viral entry. In this review, we highlight recent advances in the discovery and development of small-molecule entry inhibitors reported over the past five years that target viruses encoding Class 1 fusion proteins.