title: Design, synthesis, and biological evaluation of highly potent small molecule-peptide conjugates as new HIV-1 fusion inhibitors.
abstract: The small molecule fusion inhibitors N-(4-carboxy-3-hydroxyphenyl)-2,5-dimethylpyrrole (NB-2) and N-(3-carboxy-4-hydroxyphenyl)-2,5-dimethylpyrrole (A12) target a hydrophobic pocket of HIV-1 gp41 and have moderate anti-HIV-1 activity. In this paper, we report the design, synthesis, and structure-activity relationship of a group of hybrid molecules in which the pocket-binding domain segment of the C34 peptide was replaced with NB-2 and A12 derivatives. In addition, the synergistic effect between the small molecule and peptide moieties was analyzed, and lead compounds with a novel scaffold were discovered. We found that either the nonpeptide or peptide part alone showed weak activity against HIV-1-mediated cell-cell fusion, but the conjugates properly generated a strong synergistic effect. Among them, conjugates Aoc-βAla-P26 and Noc-βAla-P26 exhibited a low nanomolar IC50 in the cell-cell fusion assay and effectively inhibited T20-sensitive and -resistant HIV-1 strains. Furthermore, the new molecules exhibited better stability against proteinase K digestion than T20 and C34.
authors: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
authors: Chao
authors: C
authors: Wang
authors: Weiguo
authors: W
authors: Shi
authors: Lifeng
authors: L
authors: Cai
authors: Lu
authors: L
authors: Lu
authors: Qian
authors: Q
authors: Wang
authors: Tianhong
authors: T
authors: Zhang
authors: Jinglai
authors: J
authors: Li
authors: Zhenqing
authors: Z
authors: Zhang
authors: Kun
authors: K
authors: Wang
authors: Liang
authors: L
authors: Xu
authors: Xifeng
authors: X
authors: Jiang
authors: Shibo
authors: S
authors: Jiang
authors: Keliang
authors: K
authors: Liu
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects; D019286:Endopeptidase K / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D017433:Protein Structure, Secondary; D020449:Repetitive Sequences, Amino Acid; D054852:Small Molecule Libraries / Q000737:chemistry*; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D015700:HIV Envelope Protein gp41; D010455:Peptides; D054852:Small Molecule Libraries; C514787:gp41 protein, Human immunodeficiency virus 1; D019286:Endopeptidase K