Farley Kathleen A, Che Ye, Lira Ricardo, Jones Peter, Papaioannou Nikolaos, Hayward Matthew, Flanagan Mark E, Langille Jonathan, Liang Sidney, Pierce Betsy S, Ciszewski Gregory, Bonin Paul, Vincent Fabien, Ramsey Simeon, Hepworth David
Medicine Design, Pfizer Inc., 445 Eastern Point Rd, Groton, Connecticut 06340, United States.
Medicine Design, Pfizer Inc., 1 Portland Street, Cambridge, Massachusetts 02139, United States.
ACS Med Chem Lett. 2024 Oct 29;15(11):2060-2066. doi: 10.1021/acsmedchemlett.4c00316. eCollection 2024 Nov 14.
To gain further insight into the conformational properties of small cyclic peptides that bind to the G-protein coupled receptor C5aR1, we report here for the first time the elucidation of three peptide solution conformations using residual dipolar couplings and NMR temperature coefficients. Each of these peptides varies by at least one amino acid, adopts a different intramolecular hydrogen bonding pattern, and has a different solution conformation. The solution conformations were used in combination with a homology structure of C5aR1 as a design template for increasing the potency of peptide leads for the C5a receptor. This study provides a framework for using RDC solution conformations to guide the design of peptide mimetics that emulate the target bound state in solution to minimize the strain energy of the bound conformation and improve potency of the peptide for the target.
为了更深入地了解与G蛋白偶联受体C5aR1结合的小环肽的构象特性，我们首次在此报告利用残余偶极耦合和核磁共振温度系数阐明了三种肽的溶液构象。这些肽中的每一种至少有一个氨基酸不同，采用不同的分子内氢键模式，并且具有不同的溶液构象。溶液构象与C5aR1的同源结构结合使用，作为设计模板以提高肽类先导物对C5a受体的效力。本研究提供了一个框架，用于利用RDC溶液构象指导肽模拟物的设计，这些模拟物在溶液中模拟靶标结合状态，以最小化结合构象的应变能并提高肽对靶标的效力。
