The invention discloses a BimBH3 analogue containing D-type
amino acid and N-terminal
fatty acid acylation, a preparation method of the BimBH3 analogue and application of the BimBH3 analogue as a PTPN1 inhibitor to development of
hypoglycemic drugs. The structural general formula of the novel BimBH3 mimic
peptide analogue is shown as a formula I: # imgabs0 #, wherein Raa2 is equal to D-His, D-Leu, D-Pro, D-Ser, D-Arg, D-Gln, D-Lys, D-Trp, D-Val, D-Tyr, D-Ala, Raa3 is equal to D-Gln, Raa7 is equal to D-Arg, and Raa8 is equal to D-Allo-Ile. The mimic
peptide compound is derived from a core region of a Bim-BH3 structural domain, different D-type
amino acid site-specific replacement modification and N-terminal conjugated hexadecanoic acid modification are adopted for amino acids at the second, third, seventh and eighth sites respectively, the BimBH3 mimic
peptide modified by the D-type
amino acid is more stable and has higher
metabolic stability, and the
target binding capacity and inhibitory activity of the BimBH3 mimic peptide can still be reserved or even improved. The BimBH3 mimic peptide compound shows an excellent PTPN1 inhibitor, the ability of resisting
protease hydrolase and various digestive enzymes is also remarkably improved, and the BimBH3 mimic peptide compound has longer
pharmacological action time and can play a potential long-acting hypoglycemic role through
subcutaneous injection or
oral administration. The compound is completely prepared by a polypeptide
solid-
phase synthesis method, and an obtained crude product is subjected to semi-preparative liquid
chromatography purification and freeze-
drying to obtain a target compound.