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Updated: Sep 27, 2026

A High-throughput Cre-Lox Activated Viral Membrane Fusion Assay to Identify Inhibitors of HIV-1 Viral Membrane Fusion
Published on: August 14, 2018
Novel HIV fusion-inhibitory lipopeptides exhibit dramatically improved activity against resistant mutants
Yuanmei Zhu1, Ting Chen2, Nian Liu1
1National Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 102629, China.
Abstract:
LP-98 is a potent HIV fusion-inhibitory lipopeptide but displays reduced activity against resistant mutants. In this study, we rationally designed a group of new lipopeptides by adding different lengths of gp41 pocket-binding sequence into the N-terminus of LP-98. It was found that a single pocket-inserting residue Ile124 critically determined the anti-HIV activity, whereas incorporation of additional pocket-inserting residues Trp120 and Trp117 generated lipopeptides with greatly reduced activity. As indicated by LP-101 and LP-108, while Ile124-modified lipopeptides maintained or improved the inhibitory activity of LP-98 against divergent HIV and SIV isolates, they had dramatically increased potencies on the resistant mutants. In both the HIV-infected humanized mice and SIV-infected rhesus macaques, LP-101 efficiently suppressed viral replication below detection limits. Mechanically, Ile124-modified lipopeptides exhibited greatly enhanced binding affinity with a target-mimic peptide N44. We determined the crystal structure of LP-101 bound to N44, revealing its N-terminal residues penetrating deeper into the gp41 pocket, forming enhanced interactions with the target site. Molecular dynamics simulations also revealed its flexible N-terminus enables adaptive binding to the wild-type and resistant mutants, with improved binding free energies. Therefore, our data inform the structure-activity relationship of this class of HIV fusion inhibitors and offer new candidates for drug development.
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