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

Bleasdale, John E.; Ogg, D.; Palazuk, Barbara J.; Jacob, C.S; Swanson, Michael; Wang, X.Y; Thompson, David P.; Conradi, Robert A.; Mathews, W R; Laborde, A. L.; Stuchly, C. W.; Heijbel, Anna; Bergdahl, Katrin; Bannow, Carol A.; Smith, Carli; Svensson, Carina E.; Liljebris, Charlotta; Schostarez, Heinrich J.; May, Paul D.; Stevens, Frits C.; Larsen, Scott D.

doi:10.1021/bi002865v

Cited by 85 publications

(79 citation statements)

References 49 publications

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“…These observations have been extended further in the present analysis, demonstrating that selectivity for either of these enzymes must be achieved by addressing other areas. It is of significant interest that despite the high sequence and structural identity of TC-PTP and PTP1B, we and others (34) have been able to identify areas close to the active site that are structurally different and which might be utilized in developing PTP1B-or TC-PTP-selective inhibitors in the future. We speculate that the intrinsic differences in substrate recognition discussed above may at least in part be attributed to these areas.…”

Section: Discussionmentioning

confidence: 99%

Structure Determination of T Cell Protein-tyrosine Phosphatase

Iversen¹,

Möller²,

Pedersen³

et al. 2002

Journal of Biological Chemistry

162

151

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Protein-tyrosine phosphatase 1B (PTP1B) has recently received much attention as a potential drug target in type 2 diabetes. This has in particular been spurred by the finding that PTP1B knockout mice show increased insulin sensitivity and resistance to diet-induced obesity. Surprisingly, the highly homologous T cell protein-tyrosine phosphatase (TC-PTP) has received much less attention, and no x-ray structure has been provided. We have previously co-crystallized PTP1B with a number of low molecular weight inhibitors that inhibit TC-PTP with similar efficiency. Unexpectedly, we were not able to co-crystallize TC-PTP with the same set of inhibitors. This seems to be due to a multimerization process where residues 130 -132, the DDQ loop, from one molecule is inserted into the active site of the neighboring molecule, resulting in a continuous string of interacting TC-PTP molecules. Importantly, despite the high degree of functional and structural similarity between TC-PTP and PTP1B, we have been able to identify areas close to the active site that might be addressed to develop selective inhibitors of each enzyme.Protein-tyrosine phosphatases (PTPs) 1 are key regulators of signal transduction processes (1, 2). The family of classical PTPs can be divided into two broad categories as intracellular and receptor-like PTPs covering a total of 17 subtypes (3). Receptor-like PTPs contain an extracellular domain, a single transmembrane domain, and one or two cytoplasmic PTP domains. Intracellular PTPs generally contain one PTP domain and an N-or C-terminal domain that targets the enzymes to specific subcellular localizations, as exemplified by the targeting of PTP1B to the endoplasmic reticulum (4).PTP1B and TC-PTP are two closely related intracellular enzymes. PTP1B was the first protein-tyrosine phosphatase to be identified and characterized (5, 6). Shortly after this landmark event, PTP1B was cloned from a placenta cDNA library (7), and TC-PTP was cloned from a peripheral human T cell cDNA library (8). Despite its name, TC-PTP is ubiquitously expressed (9). Alternative splicing gives rise to two forms of TC-PTP that differ in the C termini, a 45-kDa form that is targeted to the nucleus and a 48-kDa form that localizes to the endoplasmic reticulum via a hydrophobic C-terminal region (10). TC-PTP is tightly regulated during the cell cycle and seems to play an important role in mitogenesis (9). In a recent study, it was shown that cellular stress causes reversible cytoplasmic accumulation of the 45-kDa form of TC-PTP (i.e. the nuclear form) (11).Although they have a sequence identity of about 74% in the catalytic domains (see Fig. 1), TC-PTP and PTP1B clearly fulfill different biological functions, as has been demonstrated in knock-out mice. Thus, although PTP1B knock-out mice show increased insulin sensitivity and resistance to diet-induced obesity and are viable with a normal life span (12, 13), TC-PTP knock-out mice die at 3-5 weeks of age (14).In accordance with these in vivo observations, substrate trapping experiment...

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Section: Discussionmentioning

confidence: 99%

Structure Determination of T Cell Protein-tyrosine Phosphatase

Iversen¹,

Möller²,

Pedersen³

et al. 2002

Journal of Biological Chemistry

162

151

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“…In this context it should also be mentioned that the very nature of the PTP active site with a catalytically essential cysteine, which is susceptible to redox regulation, may confound the evaluation of potential lead structures. Thus, it is now becoming clear that the high hit rates, which are often observed when screening for PTP inhibitors, in many cases are due to oxidation or alkylation of the active site cysteine rather than to true inhibition (16,24). To avoid such problems and to create a general technological platform, we have here explored the possibility of utilizing a general, low molecular weight, active site-directed PTP inhibitor as a synthetic scaffold for the design of inhibitors that are selective for other PTPs than PTP1B.…”

Section: Discussionmentioning

confidence: 99%

“…The field has advanced significantly by a number of x-ray crystallographic structures (reviewed in Refs. 3, 13, and 14), and several research groups have successfully used structure-based designs to synthesize active site-directed, selective PTP1B inhibitors (15)(16)(17)(18)(19)(20). Most important, two groups have demonstrated recently that it is possible to develop compounds that are selective for PTP1B over the highly homologous T cell-PTP (21,22), thereby lending support to the view that selective inhibitors, which discriminate between even closely related PTPs, are within reach.…”

mentioning

confidence: 99%

“…compounds that are not true inhibitors. Indeed, when searching for PTP inhibitors, it is a common experience among laboratories that perform high throughput screenings to get high hit rates, which in many cases are caused by oxidation or alkylation of the active site cysteine (16,24). 2 Although compounds that irreversibly and/or more broadly in a time-dependent manner modify PTPs may still be useful in the clinic (25)(26)(27), structurebased optimization is often difficult, if not impossible.…”

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confidence: 99%

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Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

Lund

Andersen

Iversen

et al. 2004

Journal of Biological Chemistry

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Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors. In contrast, little attention has been given to other potential drug targets within the PTP family. Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses with wild type and mutant PTPs, we describe the development of a general, low molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor that displays more than 100-fold selectivity for PTP␤ over PTP1B. Of note, our structure-based design principles, which are based on extensive bioinformatics analyses of the PTP family, are general in nature. Therefore, we anticipate that this strategy, here applied to PTP␤, in principle can be used in the design and development of selective inhibitors of many, if not most PTPs.Protein-tyrosine phosphatases (PTPs) 1 are key regulators of signal transduction. Together with the counteracting proteintyrosine kinases, they control the phosphorylation status of many important proteins and are thereby critically involved in the regulation of fundamental cellular processes such as metabolism, cell growth, and differentiation. Aberrant tyrosine phosphorylation levels have been associated with the development of cancer, autoimmunity, and diabetes, thus indicating that PTPs might play important etiological and pathogenic roles in these diseases (1-5). In particular, two elegant studies with PTP1B knockout mice, in which increased insulin sensitivity and resistance to diet-induced obesity were observed (6, 7), indicated that PTP1B is an important negative regulator of insulin and leptin action, suggesting that inhibition of this enzyme could augment and prolong insulin and leptin signaling (8, 9). As a result, a number of academic and industrial laboratories have devoted considerable efforts toward the development of selective inhibitors of PTP1B for treatment of type 2 diabetes and obesity resulting in very significant progress (reviewed in Refs. 10 -12). The field has advanced significantly by a number of x-ray crystallographic structures (reviewed in Refs. 3, 13, and 14), and several research groups have successfully used structure-based designs to synthesize active site-directed, selective PTP1B inhibitors (15-20). Most important, two groups have demonstrated recently that it is possible to develop compounds that are selective for PTP1B over the highly homologous T cell-PTP (21, 22), thereby lending support to the view that selective inhibitors, which discriminate between even closely related PTP...

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“…2A) 30) in the ionized and unionized forms. Accordingly, the following FRED parameters were employed:…”

Section: Methodsmentioning

confidence: 99%

Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Bustanji

Taha

Almasri

et al. 2009

Biological & Pharmaceutical Bulletin

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Natural products have played an important role in treating and preventing human diseases.1) An analysis of the origin of the drugs that were launched in the last twenty-five years showed that both natural products and semi-synthetic compounds, derived from natural origin, comprised 34% of all new chemical entities, while 18% of them were synthetic mimics of natural compounds.2) Therefore, natural products are considered important sources for new drugs or lead optimization.2,3) The structural diversity of natural products combined with the fact that they were elaborated within living systems render them more "drug-like" than totally synthetic molecules. 4-7)Papaverine (Fig. 1A) is a prominent member of isoquinoline alkaloids isolated from opium poppy (Papaver somniferum L.).8) It exhibits non-selective smooth muscle relaxant effects, which prompted its widespread clinical use in the treatment of vasospasmic diseases.9-11) Papaverine increases the unidirectional K ϩ influx into muscles causing vasodilatation and muscle relaxant effects. The K ϩ flux is associated with increases in glucose uptake which could be one of the causes of hypoglycemia associated with papaverine use. 12)In a recent publication, we revealed a potent inhibitory action for berberine (Fig. 1B), another prominent isoquinoline alkaloid, against the anti-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B).13) The chemical similarity between berberine and papaverine combined with the fact that they share common biosynthetic origin, 14,15) prompted us to evaluate any possible inhibitory action of papaverine against h-PTP 1B. Furthermore, several reports have indicated that opiates, including papaverine, possess significant hypoglycemic properties. 16,17) The hypoglycemic mechanism of opiates is still uncertain. Furthermore, the hypoglycemic effect of papaverine is not well characterized using in vivo animal models.h-PTP 1B, a cytosolic non-receptor protein tyrosine phosphatase, has been implicated in the progression of diabetes because it acts as negative regulator of insulin signal transduction. h-PTP 1B directly catalyzes the dephosphorylation of cellular substrates of the insulin receptor kinase resulting in a down-regulation of insulin action. [18][19][20][21] Mice lacking functional h-PTP 1B showed enhanced tyrosine kinase activity and increased sensitivity to insulin. 22) In another animalbased approach, treatment with anti-sense oligonucleotide specific for h-PTP 1B resulted in normalization of blood glucose and insulin levels in animal models of type 2 diabetes. 23)Accordingly, h-PTP 1B inhibitors could increase insulin receptor tyrosine phosphorylation, mimic cellular and in vivo actions of insulin, and lower plasma glucose levels in diabetic animal models. [24][25][26][27] The current project commenced by computer-aided docking simulations to probe potential binding interactions within papaverine/h-PTP 1B complex. Subsequently, we validated our theoretical findings in vitro and in vivo. The structural similarity between papa...

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

Cited by 85 publications

References 49 publications

Structure Determination of T Cell Protein-tyrosine Phosphatase

Structure Determination of T Cell Protein-tyrosine Phosphatase

Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

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