Enfuvirtide

Enfuvirtide (Fuzeon) is an FDA-approved 36 amino acid synthetic peptide that was the first HIV fusion inhibitor and the first of an entirely new class of antiretroviral drugs. Approved in 2003, it is used as part of combination antiretroviral therapy for treatment-experienced adults and pediatric patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

Enfuvirtide is a biomimetic peptide derived from the C-terminal heptad repeat (HR2) region of HIV-1 gp41. During viral entry, gp41 undergoes a conformational rearrangement in which its HR1 and HR2 domains fold together to form a six-helix bundle, driving fusion of the viral and host cell membranes. Enfuvirtide binds to the HR1 domain of gp41 in a sequence-specific manner, sterically blocking the HR2 domain from interacting with HR1. By preventing six-helix bundle formation, enfuvirtide arrests the fusion process before viral RNA can be delivered into the CD4+ T lymphocyte, effectively halting infection at the cell entry step. This pre-fusion mechanism is entirely distinct from all other antiretroviral drug classes, preserving activity against strains resistant to reverse transcriptase or protease inhibitors.

The pivotal TORO-1 and TORO-2 Phase III trials (2,000+ treatment-experienced patients) demonstrated that enfuvirtide added to an optimized background regimen reduced HIV-1 RNA by an additional 1.0 log10 copies/mL compared to background regimen alone at 24 weeks. FDA approval was granted in 2003. Resistance emerges via mutations in the HR1 region of gp41. Its use is now largely reserved for heavily treatment-experienced patients with multidrug-resistant HIV, given that newer oral agents have simplified regimens considerably.