Authors
Yuanmei Zhu, Ting Chen, Nian Liu, Xiuzhu Geng, Na Li, Jiahan Lu, Fei Wang, Jiasen Yang, Zhe Cong, Bo Qin, Huihui Chong, Sheng Cui, Jing Xue, Yuxian He
Published in
Molecular therapy : the journal of the American Society of Gene Therapy. Sep 26, 2026. Epub Sep 26, 2026.
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.
PMID:
42798179
Bibliographic data and abstract were imported from PubMed on 26 Sep 2026.
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