Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-10-29 DOI:10.1021/acsmedchemlett.4c0031610.1021/acsmedchemlett.4c00316

Kathleen A. Farley*, Ye Che, Ricardo Lira, Peter Jones, Nikolaos Papaioannou, Matthew Hayward, Mark E. Flanagan, Jonathan Langille, Sidney Liang, Betsy S. Pierce, Gregory Ciszewski, Paul Bonin, Fabien Vincent, Simeon Ramsey and David Hepworth,

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Abstract

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.

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利用残余双极偶联的溶液构象分析设计环肽 C5aR1 拮抗剂

为了进一步深入了解与 G 蛋白偶联受体 C5aR1 结合的小环肽的构象特性，我们在此首次报告了利用残余偶极耦合和核磁共振温度系数阐明的三种肽溶液构象。每种肽至少有一个氨基酸不同，采用不同的分子内氢键模式，具有不同的溶液构象。这些溶液构象与 C5aR1 的同源结构相结合，用作提高 C5a 受体多肽先导物效力的设计模板。本研究提供了一个框架，利用 RDC 溶液构象指导多肽模拟物的设计，模拟目标物在溶液中的结合态，从而最大限度地降低结合构象的应变能，提高多肽对目标物的效力。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.