title: Design of a highly potent HIV-1 fusion inhibitor targeting the gp41 pocket.
abstract: OBJECTIVE
  T20 (Enfuvirtide), which is a 36-residue peptide derived from the C-terminal heptad repeat (CHR) of gp41, is the only clinically available HIV-1 fusion inhibitor, but it easily induces drug resistance, which calls for next-generation drugs.
  
  
  METHODS
  We recently demonstrated that the M-T hook structure can be used to design a short CHR peptide that specifically targets the conserved gp41 pocket rather than the T20-resistant sites. We attempted to develop more potent HIV-1 fusion inhibitors based on the structure-activity relationship of MT-SC22EK.
  
  
  METHODS
  Multiple biophysical and functional approaches were performed to determine the structural features, binding affinities and anti-HIV activities of the inhibitors.
  
  
  RESULTS
  The 23-residue peptide HP23, which mainly contains the M-T hook structure and pocket-binding sequence, showed a helical and trimeric state in solution. HP23 had dramatically improved binding stability and antiviral activity, and it was the most potent inhibitor of the M-T hook-modified and unmodified control peptides. More promisingly, HP23 was highly active in the inhibition of diverse HIV-1 subtypes, including T20 and MT-SC22EK resistant HIV-1 mutants, and it exhibited a high genetic barrier to the development of resistance.
  
  
  CONCLUSIONS
  Our studies delivered an ideal HIV-1 fusion inhibitor that specifically targeted the highly conserved gp41 pocket and possessed potent binding and antiviral activity. Furthermore, HP23 can serve as a critical tool to explore the mechanisms of HIV-1 fusion 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, P. R. China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.forename: Zonglin
authors.initials: Z
authors.lastname: Qiu
authors.forename: Yang
authors.initials: Y
authors.lastname: Su
authors.forename: Lingli
authors.initials: L
authors.lastname: Yang
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D023581:HIV Fusion Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; C514787:gp41 protein, Human immunodeficiency virus 1