Background In the early of 1990’s, several peptides overlapping gp41 CHR region, including SJ-2176, T20, and C34 were reported to have potent HIV-1 fusion inhibitory activity. T20 (generic name: enfuvirtide) was approved by the U.S. FDA as the first HIV-1 fusion inhibitory peptide-based anti-HIV drug. However, its clinical application is limited because of its low potency and low genetic barrier to resistance. Furthermore, its mechanism of action is still elusive. Therefore, it is essential to define T20’s mechanism of action, based on which a new analogous peptide with improved antiviral activity can be designed.

Methods The inhibitory activity of peptides on 6HB formation was tested in a temperature-controlled cell-cell fusion assay by flow cytometry using 6HB-specific mAb 2G8; on HIV-1 infection and fusion was assessed by p24 and cell-cell fusion assays. Interaction between different peptides or peptide and antibody was evaluated by ELISA.

Results T20 could inhibit 6HB formation at early, but not late, stage of HIV-1 fusion, while T1144 was effective at both stages. T20-SF is much more effective than T20 in binding to FP-P and inhibiting infection of HIV-1, including T20-resistant strains, and FP-P-mediated hemolysis.

Conclusion In the early of 1990’s, several peptides overlapping gp41 CHR region, including SJ-2176 (residues 630–659), T20 (residues 638–673), and C34 (residues 628–661) were reported to have potent HIV-1 fusion inhibitory activity. T20 (generic name: enfuvirtide) was approved by the U.S. FDA as the first HIV-1 fusion inhibitory peptide-based anti-HIV drug. However, its clinical application is limited because of its low potency and low genetic barrier to resistance. Furthermore, its mechanism of action is still elusive. Therefore, it is essential to define T20’s mechanism of action, based on which a new analogous peptide with improved antiviral activity against divergent HIV-1 strains, including those resistant to T20.

Disclosure No significant relationships.