Figure 1. HIV fusion and entry: how does enfuvirtide work? (A) In this stylized representation, HIV fusion with the target cell starts with the attachment of gp120 to the N-terminal domain of the CD4+ receptors. (B) Once attached, gp120 undergoes a conformational change that unmasks the binding site for the cell coreceptor (CCR5 or CXCR4). (C) Once the virus is bound to both CD4+ and chemokine receptors, a conformational change exposes the N-terminal hydrophobic region of gp41 to the CD4+ cell membrane. This allows the two heptad repeat sequences (HR1 and HR2) of gp41 to interact, resulting in formation of a hairpin, also referred to as a coiled-coil bundle. (D) The hairpin structure brings the virus and cell membranes together, mediating fusion of virus and cell. (E) In the presence of enfuvirtide (T20), the two heptad regions cannot interact with each other because the drug competitively binds to HR1, stopping formation of the hairpin structure necessary for gp41 to initiate fusion between HIV and the host cell.
Figure 2. Inhibition of gp41 by enfuvirtide in HIV fusion process. HR 1 = heptad repeat 1; HR 2 = heptad repeat 2. Step 1: enfuvirtide (T-20) inhibits competitively the HR 1 region by binding to it. Step 2: once T-20 binds to HR1, it prevents HR1 from interacting with HR2, and therefore inhibits formation of the coiled-coil bundle necessary to initiate fusion of HIV and the host cell.
Figure 3. Effect of intravenous enfuvirtide monotherapy on plasma HIV RNA concentrations (TRI-001 clinical trial). A significant difference from baseline was measured on day 15 for all groups (p<0.05), and for those receiving 100 mg alone (p<0.05). The HIV RNA (viral load) was measured by bDNA assay. (Adapted from reference 15.)
Figure 4. Subcutaneous injection survey used in phase III clinical trials.