Tamamura Hirokazu, Hiramatsu Kenichi, Kusano a Shuichi, Terakubo Shigemi, Yamamoto Naoki, Trent John O, Wang Zixuan, Peiper Stephen C, Nakashima Hideki, Otaka Akira, Fujii Nobutaka
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Org Biomol Chem. 2003 Nov 7;1(21):3656-62. doi: 10.1039/b306473p.
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.
一种肽类CXCR4拮抗剂T140能有效阻断HIV-1的T细胞系嗜性毒株（X4-HIV-1）进入靶细胞。在本研究中，合成了一系列用Glu（D-Glu）和/或L-瓜氨酸（Cit）取代碱性氨基酸残基的T140衍生物，以减少非特异性结合和细胞毒性。其中，TE14011（C末端酰胺化的[Cit6，D-Glu8]-T140）表现出较强的抗HIV活性和较低的细胞毒性。发现TE14011在小鼠血清中稳定，但在大鼠肝匀浆中不稳定，这是由于其亲本肽的N末端Arg1-Arg2-L-3-（2-萘基）丙氨酸（Nal）3残基缺失所致。TE14011的N末端乙酰化导致了一种新型先导化合物Ac-TE 14011的产生，该化合物具有高选择性指数以及在血清和肝匀浆中增加的稳定性。
