Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives.
Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives.
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DOI：
10.1039/b306473p
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发表时间：
2003-10
影响因子：
3.2
通讯作者：
H. Tamamura;K. Hiramatsu;S. Kusano;S. Terakubo;N. Yamamoto;J. Trent;Zixuan Wang;S. Peiper;H. Nakashima;A. Otaka;N. Fujii
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文献类型：
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作者：
H. Tamamura;K. Hiramatsu;S. Kusano;S. Terakubo;N. Yamamoto;J. Trent;Zixuan Wang;S. Peiper;H. Nakashima;A. Otaka;N. Fujii
肽CXCR 4拮抗剂T140有效地阻断HIV-1的T细胞系嗜性株（X4-HIV-1）进入靶细胞。在这项研究中，一系列的T140衍生物，取代的基本氨基酸残基与谷氨酸（D-谷氨酸）和/或L-瓜氨酸（Cit），以减少非特异性结合和细胞毒性。其中，TE 14011（[Cit 6，D-Glu 8]-T140，C-末端为酰胺）具有较强的抗HIV活性和较低的细胞毒性。发现TE 14011在小鼠血清中稳定，但在大鼠肝匀浆中不稳定，这是由于从亲本肽中缺失N-末端Arg 1-Arg 2-L-3-（2-萘基）丙氨酸（Nal）3残基。TE 14011的N-末端乙酰化导致开发了一种新型先导化合物Ac-TE 14011，其具有高选择性指数以及在血清和肝匀浆中增加的稳定性。
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.