DESIGN OF A POTENT PEPTIDE INHIBITOR OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR TYROSINE KINASE UTILIZING SEQUENCES BASED ON THE NATURAL PHOSPHORYLATION SITES OF PHOSPHOLIPASE C-GAMMA-1
Dw. Fry et al., DESIGN OF A POTENT PEPTIDE INHIBITOR OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR TYROSINE KINASE UTILIZING SEQUENCES BASED ON THE NATURAL PHOSPHORYLATION SITES OF PHOSPHOLIPASE C-GAMMA-1, Peptides, 15(6), 1994, pp. 951-957
Peptides that possess primary sequences identical to segments surround
ing the natural phosphorylation sites of phospholipase C-gamma 1 (i.e.
, tyrosines 472, 771, 783, and 1284) have been synthesized and evaluat
ed with respect to substrate kinetics for the epidermal growth factor
receptor tyrosine kinase. A peptide that was based on tyrosine 472 was
the superior substrate in terms of lowest K-m value at 37 mu M and ha
d the following amino acid sequence: -Lys-Leu-Ala-Glu-Gly-Ser-Ala-Tyr(
472)-Glu-Glu-Val. This peptide sequence was used as a foundation to ma
ke amino acid substitutions and/or chemical modifications directed tow
ard the synthesis of a potent peptide inhibitor. As a result, a nine a
mino acid peptide was synthesized having a K-i of 10 mu M.