FIBROBLAST GROWTH FACTOR 1 PROTEIN FRAGMENTS AND METHODS OF USE

摘要

The present invention relates to a chimeric protein that includes an N-terminus coupled to a C-terminus, where the N-terminus includes a portion of a paracrine fibroblast growth factor (“FGF”) and the C-terminus includes a C-terminal portion of an FGF19 molecule. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. The present invention also relates to pharmaceutical compositions including chimeric proteins according to the present invention, methods for treating a subject suffering from diabetes, obesity, or metabolic syndrome, and methods of screening for compounds with enhanced binding affinity for the βKlotho-FGF receptor complex involving the use of chimeric proteins of the present invention.

主权项

1. A method of treating diabetes, obesity and/or metabolic syndrome in a subject, comprising:
administering to a subject having diabetes, obesity and/or metabolic syndrome an FGF1 peptide fragment comprising at least 95% sequence identity to an amino acid sequence consisting of: amino acids 25-155 of SEQ ID NO: 1 (FGF1ΔNT); amino acids 1-155 of SEQ ID NO: 1 with a K127D, K128Q and K133V substitution (FGF1ΔHBS); or amino acids 25-155 of SEQ ID NO: 1 with a K127D, K128Q and K133V substitution (FGF1ΔNT ΔHBS), thereby treating the diabetes, obesity and/or metabolic syndrome.