title: Development of potent and long-acting HIV-1 fusion inhibitors.
abstract: T20 (enfuvirtide) is the first approved HIV entry inhibitor and currently the only viral fusion inhibitor, but its low efficacy and genetic barrier to resistance significantly limit its application, calling for a next-generation drug.
  
  
  
  On the basis of the M-T hook structure, we recently developed a short-peptide named HP23, which mainly targets the deep pocket site of gp41 and possesses highly potent antiviral activity. To improve the pharmaceutical properties of a peptide-based inhibitor, we modified HP23 by different classes of lipids including fatty acid, cholesterol, and sphingolipids. To avoid the potential problem of oxidation, the methionine residue in the M-T hook sequence of HP23 was replaced with leucine.
  
  
  
  Peptides were synthesized and their anti-HIV activity and biophysical properties were determined.
  
  
  
  A group of lipopeptides were generated with greatly improved anti-HIV activity. Promisingly, a fatty acid-conjugated lipopeptide named LP-11 showed potent and broad inhibitory activity against diverse primary HIV-1 isolates and clinically drug-resistant mutants, and it had dramatically increased ex-vivo antiviral activity and extended half-life. Also, LP-11 displayed highly enhanced α-helicity and thermal stability, and it was physically stable under high temperature and humidity.
  
  
  
  LP-11 has high potentials for clinical development and it can serve as an ideal tool for exploring the mechanisms of HIV-1 fusion and inhibition.
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, and Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Su
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
mesh_terms: D000818:Animals; D004355:Drug Stability; D057809:HEK293 Cells; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007274:Injections, Intraperitoneal; D055666:Lipopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010949:Plasma / Q000737:chemistry; D051381:Rats
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D055666:Lipopeptides