模拟同型二聚体GDF15蛋白的双环肽串联抑制GDF15- gfral - ret复合物细胞信号传导的设计

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Anaïs F M Noisier,Jenny Sandmark,Fredrik Edfeldt,Anna Backmark,Johan Broddefalk,Joanna Wandzik,Ulrik Jurva,Margareta Ek,Carina A Johansson,Louise Barlind,Jenny Gunnarsson,Janna M Bigalke,Yafeng Xue,Andrey I Frolov,Cecilia Kankkonen,Robert G Roth,Maria Fritsch,Sophie Watcham,Katerine van Rietschoten,Gemma E Mudd,Helen Harrison,Liuhong Chen,Michael J Skynner,David J Craik,Sunay V Chankeshwara,Malin Lemurell
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引用次数: 0

摘要

GDF15- gfral - ret信号复合物参与多种疾病状态,GDF15的激动作用影响代谢和体重控制,而抑制作用在癌症和恶病质等消耗性疾病中被发现。在这里,我们描述了使用结构引导设计和噬菌体展示方法发现的GDF15-GFRaL蛋白-蛋白相互作用的肽抑制剂,以防止ret诱导的信号传导。噬菌体展示提供了对GFRaL具有高亲和力的双环肽,这些双环肽被二聚体化以模拟同二聚体GDF15的双齿相互作用。在结构数据的指导下,将单体肽转化为具有小摩尔亲和力的串联Bicycle分子,类似于内源性GDF15配体。这些二聚化的蛋白质模拟物在功能分析中抑制细胞信号传导,与它们的单体对照物相比,显示出更好的药代动力学特性。这是同二聚体Bicycle分子抑制受体复合物形成,从而对抗细胞内信号反应的第一个例子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Design of Bicyclic Peptide Tandems Mimicking the Homodimeric GDF15 Protein to Inhibit GDF15-GFRaL-RET Complex Cell Signaling.
The GDF15-GFRaL-RET signaling complex is involved in a broad range of disease states, with agonistic action of GDF15 affecting metabolism and body weight control, while inhibition is indicated in cancer and wasting disorders like cachexia. Here, we describe the discovery of the peptide inhibitors of the GDF15-GFRaL protein-protein interaction to prevent RET-induced signaling using both a structure-guided design and a phage display approach. Phage display provided bicyclic peptide hits with high affinity for GFRaL, and these were dimerized to mimic the bidentate interaction of homodimeric GDF15. Guided by structural data, the monomeric peptides were converted into tandem Bicycle molecules with picomolar affinities, similar to that of the endogenous GDF15 ligand. These dimerized protein mimetics inhibited cell signaling in a functional assay and showed improved pharmacokinetic properties compared with their monomeric counterparts. This is the first example of a homodimeric Bicycle molecule inhibiting receptor complex formation, thereby antagonizing the intracellular signaling response.
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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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