Biophysical Approaches to Entry Inhibitor Antivirals with a Broad Spectrum of Action

Abstract

ABSTRACT: Antivirals have traditionally been developed to act by biochemical principles targeting proteins, such as inhibition of enzymes or protein–protein interactions. This approach has resulted in 57 clinical antivirals or boosters, and multiple others under development. However, viral infection also requires specific unique biophysical activities from the lipids in the viral envelope. These biophysical activities could also be targeted with small molecules. Several phospholipids, for example, inhibit infectivity in model systems. Such knowledge had not been applied to antiviral development until recently. However, two families of small molecules that inhibit viral infectivity by biophysical mechanisms affecting the lipids of the virion envelope were independently identified in 2010. Although they have yet to prove strong antiviral activities in vivo, and their long-term toxicological profiles have yet to be characterized, they do provide proof-of-principle that small molecule ‘drug-like’ compounds can act by biophysical principles affecting the lipids of the virion envelope.