Development of Peptide and Small-Molecule HIV-1 Fusion Inhibitors that Target gp41

It has been 25 years since the development of the first efficient HIV-1/AIDS treatment. Scientists now know more about the HIV-1 infection life cycle, and more than 30 antiretroviral drugs have been developed, including HIV-1 fusion inhibitors. Fundamental work was begun in the early 1990s and led to the development of a novel class of anti-HIV-1 drugs, culminating in a peptide known as T20, which is currently the only HIV-1 fusion inhibitor approved by the US Food and Drug Administration. However, more work needs to be done to perfect the development of peptide and small-molecule HIV fusion inhibitors, particularly those that target gp41. Herein we present a brief overview of the development of this class of anti-HIV-1 drug by focusing on the achievements, challenges, and lessons learned. We cite hallmark studies of the past and comment on future drug development.