[Difluro(phosphono)methyl]phenylalanine-containing peptide inhibitors of protein tyrosine phosphatases

Peptides containing the non-hydrolysable phosphotyrosine analogue 4-[diflur o(phosphono)methyl]phenylalanine [Phe(CF2P)] were synthesized and tested as inhibitors of the protein tyrosine phosphatases (PTPs) PTP1B, CD45, PTP be ta, LAR and SHP-1. identified peptides containing two adjacent Phe(CF2P) re sidues as potent inhibitors of PTPs. The tripeptide having the sequence Glu -Phe(CF2P)-Phe(CF2P) is a potent and selective inhibitor of PTP 1B. This pe ptide inhibits PTP1B with an IC50 of 40 nM, which is at least 100-fold lowe r than with other PTPs. A second tripeptide, Pro-Phe(CF2P)-Phe(CF2P), is mo st potent against PTP beta, with an IC50 of 200 nM, and inhibits PTP1B with an IC50 of 300 nM. These data suggest that it is possible to develop selec tive, active-site-directed, reversible, potent inhibitors of PTPs.