Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives.
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.
Tamamura
Hirokazu
H
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Hiramatsu
Kenichi
K
Kusano
a Shuichi
aS
Terakubo
Shigemi
S
Yamamoto
Naoki
N
Trent
John O
JO
Wang
Zixuan
Z
Peiper
Stephen C
SC
Nakashima
Hideki
H
Otaka
Akira
A
Fujii
Nobutaka
N
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
D009842:Oligopeptides; D019718:Receptors, CXCR4; C116977:T140 peptide