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

Content Provider	Europe PMC
Author	Pan, Jia Parlee, Sebastian D. Brunel, Florence M. Li, Pengyun Lu, Wei Perez-Tilve, Diego Liu, Fa Finan, Brian Kharitonenkov, Alexei DiMarchi, Richard D.
Copyright Year	2020
Description	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.
Abstract	Fibroblastgrowth factors 19 and 21 (FGF19 and FGF21) have biologicalactions that render them promising clinical candidates for treatmentof metabolic diseases, particularly dyslipidemia and nonalcoholicsteatohepatitis (NASH). These two atypical endocrine FGFs employ anaccessory receptor β-klotho (KLB) to signal through classicalFGF receptors (FGFRs). FGF19 and FGF21 bind to KLB via their C-terminus,to orient the N-terminus for productive interaction with FGFRs. TheC-terminal peptides have been shown to competitively inhibit thisbiological agonism. We report here an assessment of the structuralrelationship in the C-terminal sequences of FGF19 and FGF21 that ledto the identification of a sustained-acting peptide optimized forpharmacological use. It demonstrates high potency and selectivityto antagonize FGF19 and FGF21 in cells coexpressing FGFRs and KLB.This peptide was also effective in blocking FGF19 and FGF21 mediateddownstream gene expression (i.e., Fos and Egr1) in vivo. In DIO mice, this antagonistalters metabolic function as assessed by changes in body weight, foodintake, and plasma insulin. Thus, the selective inhibition of KLBcould constitute a medicinal approach to treat diseases associatedwith excess FGF19 or 21 activity and separately serve as an effectivetool to promote a deeper assessment of atypical FGF biology.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7551714&blobtype=pdf
Volume Number	3
DOI	10.1021/acsptsci.0c00100
PubMed Central reference number	PMC7551714
Issue Number	5
PubMed reference number	33073195
Journal	ACS Pharmacology & Translational Science [ACS Pharmacol Transl Sci]
e-ISSN	25759108
Language	English
Publisher	American Chemical Society
Publisher Date	2020-08-26
Access Restriction	Open
Subject Keyword	FGF19 FGF21 peptide antagonist β-klotho (KLB)
Content Type	Text
Resource Type	Article
Subject	Pharmacology (medical) Pharmacology