Gubra Aps, Hørsholm, DK-2970 Hørsholm, Denmark; Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
Gubra Aps, Hørsholm, DK-2970 Hørsholm, Denmark.
Peptides. 2023 Oct;168:171063. doi: 10.1016/j.peptides.2023.171063. Epub 2023 Jul 24.
Growth differentiation factor 15 (GDF15) is believed to be a major causative factor for cancer-induced cachexia. Recent elucidation of the central circuits involved in GDF15 function and its signaling through the glial cell-derived neurotrophic factor family receptor α-like (GFRAL) has prompted the interest of targeting the GDF15-GFRAL signaling for energy homeostasis and body weight regulation. Here, we applied advanced peptide technologies to identify GDF15 peptide fragments inhibiting GFRAL signaling. SPOT peptide arrays revealed binding of GDF15 C-terminal peptide fragments to the extracellular domain of GFRAL. Parallel solid-phase peptide synthesis allowed for generation of complementary GDF15 peptide libraries and their subsequent functional evaluation in cells expressing the GFRAL/RET receptor complex. We identified a series of C-terminal fragments of GDF15 inhibiting GFRAL activity in the micromolar range. These novel GFRAL peptide inhibitors could serve as valuable tools for further development of peptide therapeutics towards the treatment of cachexia and other wasting disorders.
生长分化因子 15（GDF15）被认为是癌症恶病质的主要致病因素。最近对 GDF15 功能及其通过神经胶质细胞衍生的神经营养因子家族受体α样（GFRAL）信号通路的中枢回路的阐明，促使人们有兴趣针对 GDF15-GFRAL 信号通路来进行能量平衡和体重调节。在这里，我们应用先进的肽技术来鉴定抑制 GFRAL 信号的 GDF15 肽片段。SPOT 肽阵列显示 GDF15 C 端肽片段与 GFRAL 的细胞外结构域结合。平行固相肽合成允许生成互补的 GDF15 肽文库，并在表达 GFRAL/RET 受体复合物的细胞中对其进行功能评估。我们鉴定了一系列在微摩尔范围内抑制 GFRAL 活性的 GDF15 C 端片段。这些新型 GFRAL 肽抑制剂可用作进一步开发肽治疗剂的有价值工具，用于治疗恶病质和其他消耗性疾病。
