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 (FGF1ΔHBS). 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 lowering activity and adipose tissue remodeling were analyzed in normal and diabetic mice and monkeys. FINDINGS: The melting temperature of the engineered chimera (FGF1ΔHBS-FGF21C-tail) increased by ∼22 °C relative to wild-type FGF21 (FGF21WT), and resulted in a ∼5-fold increase in half-life in vivo. The chimera also acquired an ability to bind the FGFR1c isoform - the principal receptor that mediates the metabolic actions of FGF21 - and consequently was dramatically more effective than FGF21WT in correcting hyperglycemia and in ameliorating insulin resistance in db/db mice. Our chimeric FGF21 also exerted a significant beneficial effect on glycemic control in spontaneous diabetic cynomolgus monkeys. INTERPRETATION: Our study describes a structure-based chimerisation approach that effectively mitigates both the intrinsically weak receptor binding affinities and short half-lives of endocrine FGFs, and advance the development of the FGF21 hormone into a potentially useful drug for Type 2 diabetes.
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Authors | Longwei Zhao, Jianlou Niu, Huan Lin, Jing Zhao, Yang Liu, Zihui Song, Congshang Xiang, Xiaojie Wang, Yong Yang, Xiaokun Li, Moosa Mohammadi, Zhifeng Huang |
Journal | EBioMedicine
(EBioMedicine)
Vol. 48
Pg. 462-477
(Oct 2019)
ISSN: 2352-3964 [Electronic] Netherlands |
PMID | 31631034
(Publication Type: Journal Article)
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Copyright | Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Biomarkers
- Insulin
- Recombinant Proteins
- fibroblast growth factor 21
- Fibroblast Growth Factors
- Receptor, Fibroblast Growth Factor, Type 1
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Topics |
- Adipocytes
(metabolism)
- Animals
- Biomarkers
- Chromatography, High Pressure Liquid
- Disease Models, Animal
- Fibroblast Growth Factors
(chemistry, genetics, metabolism)
- Gene Expression
- Humans
- Insulin
(metabolism)
- Male
- Metabolic Diseases
(drug therapy, etiology, metabolism)
- Mice
- Models, Molecular
- Paracrine Communication
(drug effects)
- Protein Binding
- Protein Conformation
- Protein Interaction Domains and Motifs
- Receptor, Fibroblast Growth Factor, Type 1
(chemistry, genetics, metabolism)
- Recombinant Proteins
- Structure-Activity Relationship
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