title: Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket.
abstract: Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell-cell fusion and infection.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian District, Beijing 100850, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Bai
authors.forename: Huifang
authors.initials: H
authors.lastname: Xue
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Lifeng
authors.initials: L
authors.lastname: Cai
authors.forename: Jiayin
authors.initials: J
authors.lastname: Qiu
authors.forename: Shuangyu
authors.initials: S
authors.lastname: Bi
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
authors.forename: Maosheng
authors.initials: M
authors.lastname: Cheng
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
authors.forename: Keliang
authors.initials: K
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors