Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP₃ over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy

Enfuvirtide (T₂₀), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP₃, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T₂₀, and had remarkably longer in vivo half-life than T₂₀. While the preexisting antibodies in HIV-infected patients significantly suppressed T₂₀'s antiviral activity, these antibodies neither recognized AP₃, nor attenuated its anti-HIV-1 activity. Structurally different from T₂₀, AP₃ could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP₃ form a hook-like structure to stabilize interaction between AP₃ and NHR helices. Therefore, AP₃ has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.