Design of Artificial Peptide Against HIV-1 Based on the Heptad-Repeat Rules and Membrane-Anchor Strategies

<b>Objective:</b> The six-helix bundle (6-HB) is critical for HIV-1 membrane fusion. To disrupt this process, peptide inhibitors have been meticulously designed to target interactions within the 6-HB regions, thereby blocking membrane fusion and exerting inhibitory effects. Current peptide inhibitors like Enfuvirtide suffer from drug resistance and short in vivo half-life. This study aims to design novel anti-HIV-1 peptides by integrating heptad-repeat rules and membrane-anchor strategies. <b>Methods:</b> Artificial peptides were designed using HR rules from the HIV-1 gp41 6-HB motif and membrane-anchor modifications. <b>Results:</b> EK35S-Palm has emerged as a highly promising candidate for HIV-1 inhibition, exhibiting robust binding affinity to the target and effectively impeding the 6-HB spontaneous formation. <b>Discussion:</b> HR-based design avoids viral sequence homology, and membrane anchoring enhances local agent concentration, improving pharmacokinetics. The HR binding and membrane stabilization of EK35S-Palm provide synergistic inhibition. <b>Conclusions:</b> Integrating HR structural design with membrane-anchor strategies yields potent HIV-1 fusion inhibitors. EK35S-Palm demonstrates superior efficacy and stability over current therapies. These approaches hold great potential for overcoming the current therapy limitations and advancing the more effective and durable HIV-1 fusion inhibitors.