Peptides containing phosphonate based, non-hydrolyzable phosphotyrosyl (pTyr) mimetics and also arylphosphonate-containing small molecules have been previously shown to be competitive inhibitors of protein-tyrosine phosphatases (PTPases). These agents suffer from low cellular penetration which is partially attributable to ionization of the phosphonate group at physiological pH. We have developed the non-phosphorous containing pTyr mimetic, L-O-malonyltyrosine (L-OMT) and it's fluoro-derivative (FOMT) and incorporated them into a hexamer peptide Ac-D-A-D-E-X-L-amide (X = L-OMT or FOMT). Both peptide derivatives potently inhibited dephosphorylation of insulin receptor by a recombinant PTPase, PTP-1B. FOMT-containing peptide showed 10-fold higher activity compared to its L-OMT analog. Prodrug protection of L-OMT or FOMT moieties as carboxylic acid diester could potentially increase cellular penetration, thereby making them valuable reagents for cellular studies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000883-02
Application #
5200373
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code