[Difluro(phosphono)methyl]phenylalanine-containing peptide inhibitors of protein tyrosine phosphatases.
Peptides containing the non-hydrolysable phosphotyrosine analogue 4-[difluro(phosphono)methyl]phenylalanine [Phe(CF2P)] were synthesized and tested as inhibitors of the protein tyrosine phosphatases (PTPs) PTP1B, CD45, PTPbeta, LAR and SHP-1. We have identified peptides containing two adjacent Phe(CF2P) residues as potent inhibitors of PTPs. The tripeptide having the sequence Glu-Phe(CF2P)-Phe(CF2P) is a potent and selective inhibitor of PTP1B. This peptide inhibits PTP1B with an IC50 of 40 nM, which is at least 100-fold lower than with other PTPs. A second tripeptide, Pro-Phe(CF2P)-Phe(CF2P), is most potent against PTPbeta, with an IC50 of 200 nM, and inhibits PTP1B with an IC50 of 300 nM. These data suggest that it is possible to develop selective, active-site-directed, reversible, potent inhibitors of PTPs.
Desmarais
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Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, P.O. Box 1005, Pointe-Claire, Dorval, Quebec H9R 4P8, Canada.
Friesen
R W
RW
Zamboni
R
R
Ramachandran
C
C
D020134:Catalytic Domain / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
D009842:Oligopeptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C089985:phosphonodifluoromethylphenylalanine; D010649:Phenylalanine; D066246:ErbB Receptors; D017027:Protein Tyrosine Phosphatases