Fibroblast growth factors 19 and 21 (FGF19 and FGF21) have biological actions that render them promising clinical candidates for treatment of metabolic diseases, particularly dyslipidemia and nonalcoholic steatohepatitis (NASH). These two atypical endocrine FGFs employ an accessory receptor β-klotho (KLB) to signal through classical FGF receptors (FGFRs). FGF19 and FGF21 bind to KLB via their C-terminus, to orient the N-terminus for productive interaction with FGFRs. The C-terminal peptides have been shown to competitively inhibit this biological agonism. We report here an assessment of the structural relationship in the C-terminal sequences of FGF19 and FGF21 that led to the identification of a sustained-acting peptide optimized for pharmacological use. It demonstrates high potency and selectivity to antagonize FGF19 and FGF21 in cells coexpressing FGFRs and KLB. This peptide was also effective in blocking FGF19 and FGF21 mediated downstream gene expression (i.e., Fos and Egr1) in vivo. In DIO mice, this antagonist alters metabolic function as assessed by changes in body weight, food intake, and plasma insulin. Thus, the selective inhibition of KLB could constitute a medicinal approach to treat diseases associated with excess FGF19 or 21 activity and separately serve as an effective tool to promote a deeper assessment of atypical FGF biology.

中文翻译：

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β-Klotho 肽抑制剂作为成纤维细胞生长因子 19 和 21 拮抗剂的优化

成纤维细胞生长因子 19 和 21（FGF19 和 FGF21）具有生物学作用，使其成为治疗代谢疾病，特别是血脂异常和非酒精性脂肪性肝炎 (NASH) 的有希望的临床候选物。这两种非典型内分泌 FGF 采用辅助受体 β-klotho (KLB) 通过经典 FGF 受体 (FGFR) 发出信号。FGF19 和 FGF21 通过其 C 端与 KLB 结合，以定位 N 端以与 FGFR 进行有效的相互作用。已显示 C 端肽竞争性地抑制这种生物激动作用。我们在此报告对 FGF19 和 FGF21 的 C 端序列中结构关系的评估，这导致鉴定为药理学用途优化的持续作用肽。它在共表达 FGFRs 和 KLB 的细胞中表现出拮抗 FGF19 和 FGF21 的高效力和选择性。该肽还可有效阻断 FGF19 和 FGF21 介导的下游基因表达（即，Fos和Egr1 )体内。在 DIO 小鼠中，根据体重、食物摄入和血浆胰岛素的变化，这种拮抗剂会改变代谢功能。因此，KLB 的选择性抑制可以构成治疗与过量 FGF19 或 21 活性相关的疾病的药物方法，并单独作为促进对非典型 FGF 生物学进行更深入评估的有效工具。