Small Molecule Peptidomimetics Containing a Novel Phosphotyrosine Bioisostere Inhibit Protein Tyrosine Phosphatase 1B and Augment Insulin Action

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• 作者：John E. Bleasdale ; Derek Ogg ; Barbara J. Palazuk ; Cynthia S. Jacob ; Michael L. Swanson ; Xin-Yuan Wang ; David P. Thompson ; Robert A. Conradi ; W. Rodney Mathews ; Alice L. Laborde ; Christopher W. Stuchly
• 刊名：Biochemistry
• 出版年：2001
• 出版时间：May 15, 2001
• 年：2001
• 卷：40
• 期：19
• 页码：5642 - 5654
• 全文大小：303K
• 年卷期：v.40,no.19(May 15, 2001)
• ISSN：1520-4995

文摘

Protein tyrosine phosphatase 1B (PTP1B) attenuates insulin signaling by catalyzing dephosphorylation of insulin receptors (IR) and is an attractive target of potential new drugs for treating theinsulin resistance that is central to type II diabetes. Several analogues of cholecystokinin^26-33 (CCK-8)were found to be surprisingly potent inhibitors of PTP1B, and a common N-terminal tripeptide, N-acetyl-Asp-Tyr(SO₃H)-Nle-, was shown to be necessary and sufficient for inhibition. This tripeptide was modifiedto reduce size and peptide character, and to replace the metabolically unstable sulfotyrosyl group. Thisled to the discovery of a novel phosphotyrosine bioisostere, 2-carboxymethoxybenzoic acid, and toanalogues that were >100-fold more potent than the CCK-8 analogues and >10-fold selective for PTP1Bover two other PTP enzymes (LAR and SHP-2), a dual specificity phosphatase (cdc25b), and a serine/threonine phosphatase (calcineurin). These inhibitors disrupted the binding of PTP1B to activated IR invitro and prevented the loss of tyrosine kinase (IRTK) activity that accompanied PTP1B-catalyzeddephosphorylation of IR. Introduction of these poorly cell permeant inhibitors into insulin-treated cellsby microinjection (oocytes) or by esterification to more lipophilic proinhibitors (3T3-L1 adipocytes andL6 myocytes) resulted in increased potency, but not efficacy, of insulin. In some instances, PTP1B inhibitorswere insulin-mimetic, suggesting that in unstimulated cells PTP1B may suppress basal IRTK activity.X-ray crystallography of PTP1B-inhibitor complexes revealed that binding of an inhibitor incorporatingphenyl-O-malonic acid as a phosphotyrosine bioisostere occurred with the mobile WPD loop in the openconformation, while a closely related inhibitor with a 2-carboxymethoxybenzoic acid bioisostere boundwith the WPD loop closed, perhaps accounting for its superior potency. These CCK-derived peptidomimeticinhibitors of PTP1B represent a novel template for further development of potent, selective inhibitors,and their cell activity further justifies the selection of PTP1B as a therapeutic target.