title: The M-T hook structure increases the potency of HIV-1 fusion inhibitor sifuvirtide and overcomes drug resistance.
abstract: OBJECTIVE
  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.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Yao
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
authors.forename: Zonglin
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Sun
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Swiss Light Source, Paul Scherrer Institute, CH-5232 Villigen, Switzerland.
authors.forename: Meitian
authors.initials: M
authors.lastname: Wang
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Cui
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China yhe@ipb.pumc.edu.cn.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; C505768:sifuvirtide
keywords: HIV gp41; genetic barrier; peptide inhibitors; six-helix bundle