Cyclic peptides containing tryptophan and arginine as Src kinase inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Shirazi, Amir Nasrolahi¹  Tiwari, Rakesh Kumar¹  Brown, Alex²  Mandal, Dindyal¹  Sun, Gongqin²  Parang, Keykavous¹ 

[1] Univ Rhode Isl, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA

[2] Univ Rhode Isl, Dept Cell & Mol Biol, Kingston, RI 02881 USA

关键词: Arginine;    Cyclic peptides;    Src;    Tryptophan;    Tyrosine kinase;   

DOI  :  10.1016/j.bmcl.2013.03.124

来源: Elsevier

【 摘 要 】

A number of cyclic and linear peptides containing various combinations of amino acids were evaluated for their Src kinase inhibitory potency. Among all the peptides, cyclic decapeptide C[RW](5) containing alternative arginine (R) and tryptophan (W) residues was found to be the most potent Src kinase inhibitor. C[RW](5) showed higher inhibitory activity (IC50 = 2.8 mu M) than C[KW](5), L(KW)(5), C[RW](4), and C[RW](3) with IC50 values of 46.9, 69.1, 21.5, and 25.0 mu M, respectively, as determined in a fluorescence intensity-based assay. Thus, the cyclic nature, the presence of arginine, ring size, and the number of amino acids in the structure of the peptide were found to be critical in Src kinase inhibitory potency. The IC50 value of C[RW](5) was found to be 0.8 mu M in a radioactive assay using [gamma-P-32]-ATP and polyE(4)Y as the substrate. C[RW](5) was a noncompetitive Src kinase inhibitor, showing approximately fourfold more selectivity towards Src than Abl. (C) 2013 Elsevier Ltd. All rights reserved.

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