Tomita Kenji, Oishi Shinya, Ohno Hiroaki, Peiper Stephen C, Fujii Nobutaka
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
J Med Chem. 2008 Dec 11;51(23):7645-9. doi: 10.1021/jm800930w.
Kisspeptin-GPR54 signaling is involved in the suppression of cancer metastasis and regulation of hormonal secretion. Recently, matrix metalloproteinase mediated deactivation of kisspeptins through hydrolysis of the Gly-Leu peptide bond has been reported. In the present report, GPR54 agonistic peptides having several nonhydrolyzable Gly-Leu dipeptide isosteres were designed and synthesized. (E)-Alkene- and hydroxyethylene-type isostere-containing analogues maintained the original activity with higher stability in murine serum and resistance to MMP-9-mediated cleavage.
亲吻素 - GPR54信号通路参与癌症转移的抑制和激素分泌的调节。最近，有报道称基质金属蛋白酶通过水解甘氨酸 - 亮氨酸肽键介导亲吻素失活。在本报告中，设计并合成了具有几种不可水解的甘氨酸 - 亮氨酸二肽类似物的GPR54激动肽。含（E）-烯烃和羟乙烯型类似物的类似物在小鼠血清中保持了原始活性，具有更高的稳定性和对MMP - 9介导的裂解的抗性。
