Development of Small Molecule HIV-1 Fusion Inhibitors: Linking Biology to Chemistry

Human immunodeficiency virus type 1 (HIV-1) primarily infects and then destroys CD4-positive lymphocytes, leading to the acquired immunodeficiency syndrome (AIDS). Over 20 drugs, most small and orally bioavailable, have been approved, and include reverse transcriptase and protease inhibitors. In 2003, the US-FDA approved enfuvirtide (T-20), a 36-amino acid peptide derived from the C-terminal heptad repeat of the HIV-1 gp41 ectodomain. T-20 was initially identified in 1992 from biological studies, and can effectively suppress HIV-1 infection with multi-drug resistance. Currently, numerous fusion inhibitory peptides have been designed and synthesized. Some of these peptides show strong inhibition even towards HIV-1 strains resistant to T-20. These developments also facilitate basic research into the mechanisms of HIV-1 fusion, because peptide inhibition resembles the process of viral fusion with the cellular membrane. In this review, we focus on HIV-1 fusion inhibitors and the application of their development and clinical findings to the concept of "biology to chemistry" to support rational drug design for small bioavailable compounds.