AIDS (London, England) 2017 01 24() doi 10.1097/QAD.0000000000001415
During HIV-1 fusion process, the N-terminal heptad repeat (NHR) of the HIV-1 gp41 interacts with the C-terminal heptad repeat (CHR) to form the fusion active 6-helix bundle (6-HB), thus being an effective target for the design of CHR-peptide-based HIV-1 fusion inhibitors. To overcome the limitations of the simplified helix wheel model of 6-HB, we herein developed a novel HIV-1 gp41 NHR-CHR-NHR tripartite model for the rational design of HIV-1 fusion inhibitors with improved antiviral activities.
Based on the crystal structure of 6-HB, we evaluated the NHR-binding properties of each residue in CHR. In this new tripartite model, CHR residues were divided into three groups: major binding, non-binding and assistant binding sites.
Eight CHR-peptides were designed and synthesized to confirm the validity of the tripartite model. Their affinities to NHR and inhibitory activities were analyzed.
In this tripartite model, replacements in assistant binding sites either increased or decreased the inhibition of HIV-1 infection. We identified three peptides with mutations of the residues in CHR at the assistant binding sites in our tripartite model but non-binding sites in the helical wheel model. These mutant peptides had anti-HIV-1 activity up to 26-fold more potent than that of C34, a CHR-peptide designed on the basis of the helix wheel model.
These data verified the superiority and validity of our new tripartite model for the rational design of HIV-1 fusion inhibitors. This approach can be adapted for designing viral fusion inhibitors against other enveloped viruses with class-I membrane fusion protein.