Prospects and strategies for the discovery and development of small-molecule inhibitors of six-helix bundle formation in class 1 viral fusion proteins.

Class I viral fusion proteins have an important role in the fusion of viral membranes with host cell membranes, a critical step in the viral life-cycle. These proteins all have similar structural features and form six-helix bundles in their fusogenic form, a general mechanism of action for virus-cell fusion. The successful discovery of peptide-based inhibitors of fusion proteins, in addition to the US Food and Drug Administration approval of one of these inhibitors as an anti-HIV-1 drug, confirmed that the inhibition of six-helix bundle formation is a viable strategy for identifying antiviral drugs. Because peptide-based drugs have several limitations, research has been undertaken to identify potent small-molecule inhibitors of six-helix bundle formation in a variety of viruses, including HIV-1, human respiratory syncytial virus and measles virus. Small-molecule inhibitors that disrupt six-helix bundle formation and prevent viral infection have been identified. This review will focus on the discovery of these small-molecule inhibitors.