Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ 85259, United States.
Peptides. 2010 Jun;31(6):1094-8. doi: 10.1016/j.peptides.2010.02.024. Epub 2010 Mar 7.
There is a compelling need for the development of small molecule agonists acting at family B G protein-coupled receptors. A possible lead for the development of such drugs was reported when it was recognized that sequences endogenous to the amino terminus of the secretin receptor and certain other receptors in this family possess weak full agonist activity (Dong et al. Mol Pharmacol 2006;70:206-213). In the current report, we extended those observations by building the active dipeptide motif found in the secretin receptor (WD) into each position around a conformationally constrained d-amino acid-containing cyclic hexapeptide, and determining the biological activity of each peptide at the secretin receptor. Indeed, only two positions for WD around this constrained ring resulted in biological activity at the receptor, providing further insights into the structural specificity of this phenomenon. Molecular modeling supported the presence of a unique WD backbone conformation shared only by these active peptides, and provided a more constrained template for future receptor-active agonist drug development.
开发作用于 B 族 G 蛋白偶联受体的小分子激动剂具有很强的必要性。当人们意识到，分泌素受体的氨基末端内源性序列以及该家族中的某些其他受体具有较弱的完全激动剂活性时，就有可能成为此类药物开发的潜在先导化合物（Dong 等人，Mol Pharmacol 2006；70：206-213）。在本报告中，我们通过将分泌素受体（WD）中发现的活性二肽基序构建到每个位置，构建了一个构象受限的含 D-氨基酸的环状六肽，确定了每个肽在分泌素受体上的生物学活性。实际上，只有 WD 围绕这个受限环的两个位置在受体上产生了生物学活性，这为这种现象的结构特异性提供了进一步的见解。分子建模支持了存在一种独特的 WD 骨架构象，这种构象仅存在于这些具有活性的肽中，并为未来的受体活性激动剂药物开发提供了更具约束性的模板。
