title: Two M-T hook residues greatly improve the antiviral activity and resistance profile of the HIV-1 fusion inhibitor SC29EK.
abstract: BACKGROUND
  Peptides derived from the C-terminal heptad repeat (CHR) of HIV-1 gp41 such as T20 (Enfuvirtide) and C34 are potent viral fusion inhibitors. We have recently found that two N-terminal residues (Met115 and Thr116) of CHR peptides form a unique M-T hook structure that can greatly enhance the binding and anti-HIV activity of inhibitors. Here, we applied two M-T hook residues to optimize SC29EK, an electrostatically constrained peptide inhibitor with a potent anti-HIV activity.
  
  
  RESULTS
  The resulting peptide MT-SC29EK showed a dramatically increased binding affinity and could block the six-helical bundle (6-HB) formation more efficiently. As expected, MT-SC29EK potently inhibited HIV-1 entry and infection, especially against those T20- and SC29EK-resistant HIV-1 variants. More importantly, MT-SC29EK and its short form (MT-SC22EK) suffered from the difficulty to induce HIV-1 resistance during the in vitro selection, suggesting their high genetic barriers to the development of resistance.
  
  
  CONCLUSIONS
  Our studies have verified the M-T hook structure as a vital strategy to design novel HIV-1 fusion inhibitors and offered an ideal candidate for clinical development.
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.forename: Zonglin
authors.initials: Z
authors.lastname: Qiu
authors.forename: Jianping
authors.initials: J
authors.lastname: Sun
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qiao
authors.forename: Xingxing
authors.initials: X
authors.lastname: Li
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, P, R, China. yhe@ipb.pumc.edu.cn.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D017433:Protein Structure, Secondary
chemical_list: D000998:Antiviral Agents; D023581:HIV Fusion Inhibitors; D010455:Peptides; C540660:SC29EK peptide