Department of Neurosciences, University of California at San Diego, La Jolla, 92093, United States.
Bioorg Med Chem. 2013 Sep 15;21(18):5855-69. doi: 10.1016/j.bmc.2013.07.008. Epub 2013 Jul 17.
The endogenous catecholamine release-inhibitory peptide catestatin (CST) regulates events leading to hypertension and cardiovascular disease. Earlier we studied the structure of CST by NMR, molecular modeling, and amino acid scanning mutagenesis. That structure has now been exploited for elucidation of interface pharmacophores that mediate binding of CST to its target, with consequent secretory inhibition. Designed pharmacophore models allowed screening of 3D structural domains. Selected compounds were tested on both cultured catecholaminergic cells and an in vivo model of hypertension; in each case, the candidates showed substantial mimicry of native CST actions, with preserved or enhanced potency and specificity. The approach and compounds have thus enabled rational design of novel drug candidates for treatment of hypertension or autonomic dysfunction.
内源性儿茶酚胺释放抑制肽 catestatin（CST）调节导致高血压和心血管疾病的事件。早些时候，我们通过 NMR、分子建模和氨基酸扫描诱变研究了 CST 的结构。现在，该结构已被用于阐明介导 CST 与其靶标结合的界面药效团，从而导致分泌抑制。设计的药效团模型允许对 3D 结构域进行筛选。选定的化合物在培养的儿茶酚胺能细胞和高血压的体内模型上进行了测试；在每种情况下，候选物都表现出对天然 CST 作用的实质性模拟，保留或增强了效力和特异性。因此，该方法和化合物使新型候选药物的合理设计成为可能，用于治疗高血压或自主功能障碍。
