title: Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives.
abstract: A peptidic CXCR4 antagonist T140 efficiently blocks the entry of T cell line-tropic strains of HIV-1 (X4-HIV-1) into target cells. In this study, a series of T140 derivatives, replacing the basic amino acid residues with Glu (D-Glu) and/or L-citrulline (Cit), were synthesized in order to reduce non-specific binding and cytotoxicity. Among them, TE14011 ([Cit6, D-Glu8]-T140 with the C-terminal amide) exhibited strong anti-HIV activity and low cytotoxicity. TE14011 was found to be stable in mouse serum, but unstable in rat liver homogenate due to the deletion of the N-terminal Arg1-Arg2-L-3-(2-naphthyl)alanine (Nal)3 residues from the parent peptide. N-Terminal acetylation of TE14011 led to the development of a novel lead compound, Ac-TE 14011, which possesses a high selectivity index as well as increased stability in serum and liver homogenate.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hiramatsu
authors.forename: a Shuichi
authors.initials: aS
authors.lastname: Kusano
authors.forename: Shigemi
authors.initials: S
authors.lastname: Terakubo
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Wang
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Akira
authors.initials: A
authors.lastname: Otaka
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D019718:Receptors, CXCR4; C116977:T140 peptide