The M-T hook structure increases the potency of HIV-1 fusion inhibitor sifuvirtide and overcomes drug resistance.

Abstract

OBJECTIVES:

Peptides derived from the C-terminal heptad repeat (CHR) of HIV-1 gp41 are potent fusion inhibitors. We have recently demonstrated that the unique M-T hook structure preceding the pocket-binding motif of CHR peptide-based inhibitors can greatly improve their antiviral activity. In this study, we applied the M-T hook structure to optimize sifuvirtide (SFT), a potent CHR-derived inhibitor currently under Phase III clinical trials in China.

METHODS:

The peptide MT-SFT was generated by incorporating two M-T hook residues (Met-Thr) into the N-terminus of sifuvirtide. Multiple structural and functional approaches were used to determine the biophysical properties and antiviral activity of MT-SFT.

RESULTS:

The high-resolution crystal structure of MT-SFT reveals a highly conserved M-T hook conformation. Compared with sifuvirtide, MT-SFT exhibited a significant improvement in the ability to bind to the N-terminal heptad repeat, to block the formation of the six helix bundle and to inhibit HIV-1 Env-mediated cell fusion, viral entry and infection. Importantly, MT-SFT was fully active against sifuvirtide- and enfuvirtide (T20)-resistant HIV-1 variants and displayed a high genetic barrier to developing drug resistance.

CONCLUSIONS:

Our studies have verified that the M-T hook structure offers a general strategy for designing novel HIV-1 fusion inhibitors and provide new insights into viral entry and inhibition.

• Authors: Huihui Chong, Xue Yao, Zonglin Qiu, Jianping Sun, Yuanyuan Qiao, Meng Zhang, Meitian Wang, Sheng Cui, Yuxian He
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 69 Issue 10 Pg. 2759-69 (Oct 2014) ISSN: 1460-2091 [Electronic] England
• PMID: 24908047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• HIV Envelope Protein gp41
• HIV Fusion Inhibitors
• Peptides
• sifuvirtide

Topics

• Amino Acid Sequence
• Binding Sites
• Dose-Response Relationship, Drug
• Drug Resistance, Viral (genetics)
• HIV Envelope Protein gp41 (chemistry, genetics, metabolism)
• HIV Fusion Inhibitors (chemistry, pharmacology)
• HIV-1 (drug effects)
• Humans
• Inhibitory Concentration 50
• Models, Molecular
• Molecular Sequence Data
• Mutation
• Peptides (chemistry, pharmacology)
• Protein Binding
• Protein Conformation
• Protein Interaction Domains and Motifs
• Structure-Activity Relationship
• Thermodynamics
• Virus Replication (drug effects)