Title
A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly Potent in vitro, ex vivo and in vivo Antiviral Activity
Author
Huihui Chong, Jing Xue, Shengwen Xiong, Zhe Cong, Xiaohui Ding, Yuanmei Zhu, Zixuan Liu, Ting Chen, Yifan Feng, Lei He, Yan Guo, Qiang Wei, Yusen Zhou, Chuan Qin, Yuxian He
Year
2017
Journal
Journal of Virology
Abstract
Peptides derived from the C-terminal heptad repeat (CHR) region of the HIV-1 fusogenic protein gp41 are potent viral entry inhibitors, and currently enfuvirtide (T-20) is the only one for clinical use; however, emerging drug-resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, HIV-2 sequence, intra-helical salt-bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad and long-lasting antiviral activity. In in vitro studies, LP-19 efficiently inhibited HIV-1, HIV-2 and SIV-mediated cell fusion, viral entry and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants. The ex vivo studies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced the viral loads to undetectable levels in acutely and chronically SHIV-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target.
Instrument
J-815
Keywords
Circular dichroism, Secondary structure, Chemical stability, Thermal stability, Thermodynamics, Biochemistry