Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States.
Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania 19104, United States.
J Med Chem. 2021 Mar 25;64(6):3479-3492. doi: 10.1021/acs.jmedchem.1c00185. Epub 2021 Mar 6.
Corrination is the conjugation of a corrin ring containing molecule, such as vitamin B (B12) or B12 biosynthetic precursor dicyanocobinamide (Cbi), to small molecules, peptides, or proteins with the goal of modifying pharmacology. Recently, a corrinated GLP-1R agonist (GLP-1RA) exendin-4 (Ex4) has been shown to have reduced penetration into the central nervous system relative to Ex4 alone, producing a glucoregulatory GLP-1RA devoid of anorexia and emesis. The study herein was designed to optimize the lead conjugate for GLP-1R agonism and binding. Two specific conjugation sites were introduced in Ex4, while also utilizing various linkers, so that it was possible to identify Cbi conjugates of Ex4 that exhibit improved binding and agonist activity at the GLP-1R. An optimized conjugate (), comparable with Ex4, was successfully screened and subsequently assayed for insulin secretion in rat islets and in shrews for glucoregulatory and emetic behavior, relative to Ex4.
配位是将含有卟啉环的分子，如维生素 B（B12）或 B12 生物合成前体二氰钴胺酰胺（Cbi），与小分子、肽或蛋白质进行缀合，以达到修饰药理学的目的。最近，一种配位的 GLP-1R 激动剂（GLP-1RA）exendin-4（Ex4）已被证明与单独的 Ex4 相比，穿透中枢神经系统的能力降低，产生一种没有厌食和呕吐作用的葡萄糖调节 GLP-1RA。本研究旨在优化 GLP-1R 激动和结合的先导化合物。在 Ex4 中引入了两个特定的缀合位点，同时还利用了各种连接子，因此可以鉴定出 Cbi 缀合的 Ex4，其在 GLP-1R 上表现出改善的结合和激动活性。一个优化的缀合物（），与 Ex4 相当，成功地进行了筛选，并随后在大鼠胰岛和在鼩鼱中进行了胰岛素分泌的测定，以评估其相对于 Ex4 的葡萄糖调节和呕吐行为。
