Optimization of Peptide Inhibitors of β-Klotho as Antagonists of Fibroblast Growth Factors 19 and 21

Abstract

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.