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生成 GFRAL-RET 受体复合物的肽拮抗剂用于治疗 GDF15 诱导的不适。

Creation of a Peptide Antagonist of the GFRAL-RET Receptor Complex for the Treatment of GDF15-Induced Malaise.

机构信息

Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

出版信息

J Med Chem. 2023 Aug 24;66(16):11237-11249. doi: 10.1021/acs.jmedchem.3c00667. Epub 2023 Jul 28.

DOI:10.1021/acs.jmedchem.3c00667
PMID:37506293
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10461225/
Abstract

Growth differentiation factor 15 (GDF15) is a contributor to nausea, emesis, and anorexia following chemotherapy via binding to the GFRAL-RET receptor complex expressed in hindbrain neurons. Therefore, GDF15-mediated GFRAL-RET signaling is a promising target for improving treatment outcomes for chemotherapy patients. We developed peptide-based antagonists of GFRAL that block GDF15-mediated RET recruitment. Our initial library screen led to five novel peptides. Surface plasmon resonance and flow cytometric analyses of the most efficacious of this group, termed GRASP, revealed its capacity to bind to GFRAL. studies in rats revealed that GRASP could attenuate GDF15-induced nausea and anorexia resulting from cisplatin. Combined with Ondansetron, GRASP led to an even greater attenuation of the anorectic effects of cisplatin compared to either agent alone. Our results highlight the beneficial effects of GRASP as an agent to combat chemotherapy-induced malaise. GRASP may also be effective in other conditions associated with elevated levels of GDF15.

摘要

生长分化因子 15（GDF15）通过与后脑神经元表达的 GFRAL-RET 受体复合物结合，成为化疗后恶心、呕吐和厌食的原因。因此，GDF15 介导的 GFRAL-RET 信号是改善化疗患者治疗效果的有前途的靶点。我们开发了 GFRAL 的基于肽的拮抗剂，可阻断 GDF15 介导的 RET 募集。我们的初始文库筛选导致了五个新的肽。对该组中最有效的一种肽，称为 GRASP 的表面等离子体共振和流式细胞术分析表明，其能够与 GFRAL 结合。在大鼠中的研究表明，GRASP 可以减轻顺铂引起的 GDF15 诱导的恶心和厌食。与单独使用昂丹司琼相比，GRASP 联合使用可更大程度地减轻顺铂的厌食作用。我们的结果突出了 GRASP 作为对抗化疗引起的不适的药物的有益作用。GRASP 也可能对其他与 GDF15 水平升高相关的疾病有效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/041c3a6d74f1/jm3c00667_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/762aa6bc1c88/jm3c00667_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/9045243d705b/jm3c00667_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/0945596935ba/jm3c00667_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/b6962a495663/jm3c00667_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/079c87c038e3/jm3c00667_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/70ac6ad1652a/jm3c00667_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/aa69249f3606/jm3c00667_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/1dc493501d7c/jm3c00667_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/041c3a6d74f1/jm3c00667_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/762aa6bc1c88/jm3c00667_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/9045243d705b/jm3c00667_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/0945596935ba/jm3c00667_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/b6962a495663/jm3c00667_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/079c87c038e3/jm3c00667_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/70ac6ad1652a/jm3c00667_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/aa69249f3606/jm3c00667_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/1dc493501d7c/jm3c00667_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3646/10461225/041c3a6d74f1/jm3c00667_0009.jpg

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Physiol Behav. 2023 Aug 1;267:114229. doi: 10.1016/j.physbeh.2023.114229. Epub 2023 May 8.
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Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms.
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Central mechanisms of emesis: A role for GDF15.呕吐的中枢机制：生长分化因子15的作用。
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