[Difluro(phosphono)methyl]phenylalanine-containing peptide inhibitors of protein tyrosine phosphatases
[Difluro(phosphono)methyl]phenylalanine-containing peptide inhibitors of protein tyrosine phosphatases
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DOI：
10.1042/0264-6021:3370219
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发表时间：
1999-01-15
影响因子：
4.1
通讯作者：
Ramachandran, C
中科院分区：
文献类型：
--
作者：
Desmarais, S;Friesen, RW;Ramachandran, C
合成含有不可水解的磷酸酪氨酸类似物4-[二氟（膦酰基）甲基]苯丙氨酸[Phe（CF2 P）]的肽，并测试其作为蛋白酪氨酸磷酸酶（PTP）PTP 1B、CD 45、PTP β、LAR和SHP-1的抑制剂。鉴定了含有两个相邻Phe（CF2 P）残基的肽作为PTP的有效抑制剂。具有序列Glu-Phe（CF2 P）-Phe（CF2 P）的三肽是PTP 1B的有效和选择性抑制剂。这种肽抑制PTP 1B的IC 50为40 nM，比其他PTPs低至少100倍。第二种三肽Pro-Phe（CF2 P）-Phe（CF2 P）对PTP β最有效，IC 50为200 nM，抑制PTP 1B的IC 50为300 nM。这些数据表明，有可能开发选择性的，活性位点定向的，可逆的，有效的PTPs抑制剂。
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, PTP beta, LAR and SHP-1. 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 PTP 1B. 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 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 selective, active-site-directed, reversible, potent inhibitors of PTPs.