Paracrine-endocrine FGF chimeras as potent therapeutics for metabolic diseases.

ABSTRACT:

Background

The development of a clinically useful fibroblast growth factor 21 (FGF21) hormone has been impeded by its inherent instability and weak FGF receptor (FGFR) binding affinity. There is an urgent need for innovative approaches to overcome these limitations.

Methods

We devised a structure-based chimerisation strategy in which we substituted the thermally labile and low receptor affinity core of FGF21 with an HS binding deficient endocrinised core derived from a stable and high receptor affinity paracrine FGF1 (FGF1^ΔHBS). The thermal stability, receptor binding ability, heparan sulfate and βKlotho coreceptor dependency of the chimera were measured using a thermal shift assay, SPR, SEC-MALS and cell-based studies. The half-life, tissue distribution, glucose

SUBMITTER: Zhao L 

PROVIDER: S-EPMC6838362 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature