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Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2018.00051

Structural Insights into the Mechanisms of Action of Short-Peptide HIV-1 Fusion Inhibitors Targeting the Gp41 Pocket

Xiujuan Zhang1, Yuanmei Zhu2, Hao Wu3, Senyan Zhang3, Pengfei Wang3, Huihui Chong2, Jinsheng He1*, Xinquan Wang3* and  Yuxian He2*
  • 1Beijing Jiaotong University, China
  • 2Chinese Academy of Medical Sciences, China
  • 3Tsinghua University, China

The deep hydrophobic pocket of HIV-1 gp41 has been considered a drug target, but short-peptides targeting this site usually lack potent antiviral activity. By applying the M-T hook structure, we previously generated highly potent short-peptide fusion inhibitors that specifically targeted the pocket site, such as MT-SC22EK, HP23L, and LP-11. Here, the crystal structures of HP23L and LP-11 bound to the target mimic peptide N36 demonstrated the critical intrahelical and interhelical interactions, especially verifying that the hook-like conformation was finely adopted while the methionine residue was replaced by the oxidation-less prone residue leucine, and that addition of an extra glutamic acid significantly enhanced the binding and inhibitory activities. The structure of HP23L bound to N36 with two mutations (E49K and L57R) revealed the critical residues and motifs mediating drug resistance and provided new insights into the mechanism of action of inhibitors. Therefore, the present data help our understanding for the structure-activity relationship (SAR) of HIV-1 fusion inhibitors and facilitate the development of novel antiviral drugs.

Keywords: HIV-1, Fusion inhibitor, six-helix bundle, crystal structure, Resistance

Received: 31 Jan 2018; Accepted: 12 Feb 2018.

Edited by:

Chen Mingzhou, Wuhan University, China

Reviewed by:

Yusen Zhou, Beijing Institute of Microbiology and Epidemiology, China
LU LU, Fudan University, China  

Copyright: © 2018 Zhang, Zhu, Wu, Zhang, Wang, Chong, He, Wang and He. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Jinsheng He, Beijing Jiaotong University, Beijing, China, jshhe@bjtu.edu.cn
Prof. Xinquan Wang, Tsinghua University, Beijing, China, xinquanwang@mail.tsinghua.edu.cn
Prof. Yuxian He, Chinese Academy of Medical Sciences, Beijing, China, yhe@ipbcams.ac.cn