title: Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor.
abstract: Enfuvirtide (T20) is the first and only HIV-1 fusion inhibitor approved for clinical use, but it can easily induce drug resistance limiting its practical application. A novel anti-HIV peptide, termed sifuvirtide, was designed based on the three-dimensional structure of the HIV-1 gp41 fusogenic core conformation. Here we report its in vitro anti-HIV potency, its mechanism of action, as well as the results from Phase Ia clinical studies. We demonstrated that sifuvirtide inhibited HIV-1-mediated cell-cell fusion in a dose-dependent manner and exhibited high potency against infections by a wide range of primary and laboratory-adapted HIV-1 isolates from multiple genotypes with R5 or X4 phenotypes. Notably, sifuvirtide was also highly effective against T20-resistant strains. Unlike T20, sifuvirtide could efficiently block six-helix bundle formation in a dominant negative fashion. These results suggest that sifuvirtide has a different mechanism of action from that of T20. Phase Ia clinical studies of sifuvirtide (FS0101) in 60 healthy individuals demonstrated good safety, tolerability, and pharmacokinetic profiles. A single dose regimen (5, 10, 20, 30, and 40 mg) by subcutaneous injection once daily at abdominal sites was well tolerated without serious adverse events. Pharmacokinetic studies of single and multiple administration of sifuvirtide showed that its decay half-lives were 20.0 +/- 8.6 h and 26.0 +/- 7.9 h, respectively. In summary, sifuvirtide has potential to become an ideal fusion inhibitor for treatment of HIV/AIDS patients, including those with HIV-1 strains resistant to T20.
authors.affiliation: AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Haifeng
authors.initials: H
authors.lastname: Song
authors.forename: Qing
authors.initials: Q
authors.lastname: Liang
authors.forename: Dan
authors.initials: D
authors.lastname: Ju
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Weiguo
authors.initials: W
authors.lastname: Jing
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Linqi
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002681:China; D002942:Circular Dichroism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010641:Phenotype
chemical_list: D019380:Anti-HIV Agents; D010455:Peptides; C505768:sifuvirtide