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Novel protein tyrosine phosphatase 1B inhibitors: interaction requirements for improved intracellular efficacy in type 2 diabetes mellitus and obesity control

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Abstract

Resistance to the hormones insulin and leptin are hallmarks in common for type 2 diabetes mellitus and obesity. Both conditions are associated with increased activity and expression of protein tyrosine phosphatase (PTP)1B. Therefore, inhibition of PTP1B activity or down-regulation of its expression should ameliorate insulin and leptin resistance, and may hold therapeutic utility in type 2 diabetes mellitus and obesity control. This background has motivated the fervent search for PTP1B inhibitors, carried out in the recent years. The purpose of this review is to provide the most recent advances in understanding the structural details of PTP1B molecule relevant to the interactions with inhibitors, and the progress towards compounds with enhanced membrane permeability, affinity, specificity, and potency on intracellular PTP1B; several inhibitors of benefit in type 2 diabetes mellitus and obesity control are presented and discussed.

Highlights

► PTP1B, an active player in insulin and leptin resistance. ► PTP1B chemical structure, substrates, activation/inactivation. ► The structural features of PTP1B molecule relevant to the interactions with inhibitors. ► The progress towards inhibitors with enhanced membrane permeability, affinity, specificity, and potency on intracellular PTP1B.

Section snippets

PTP1B, an active player in insulin and leptin resistance

In physiologic condition, two hormones are crucial for long-term energy storage: insulin, that controls the pathways responsible for glucose uptake and lipogenesis, and leptin, that regulates food intake and peripheral energy expenditure. Resistance to insulin and leptin is the hallmark in common for type 2 diabetes mellitus and obesity, two pathologies continuously increasing in prevalence worldwide. Insulin resistance is manifest in adipocytes, skeletal muscle, and hepatocytes by defects of

PTP1B chemical structure, substrates, activation/inactivation

PTP1B (encoded by Ptpn1 gene) is a prototypical member of the PTP family of enzymes. It is a ubiquitously expressed enzyme (EC 3.1.3.48) known to dephosphorylate and control a multitude of signaling events during cell growth, differentiation, apoptosis, and cell movement.

PTP-1B is a 50 kDa monomeric enzyme containing 435 amino acids. The N-terminal domain (amino acids 1–298) includes the catalytic domain which contains two aryl phosphate-binding sites: a high-affinity catalytic site (containing

The structural features of PTP1B molecule relevant to the interactions with inhibitors

The most efficient inhibition is accomplished when the inhibitor occupies the high-affinity catalytic site of PTP1B. The latter is defined by residues 214–221 (the P-loop) and has preference for acidic residues. Therefore, inhibitors aimed to occupy the active site should be anionic charged at physiologic pH, and possess polar groups. The former most investigated PTP1B inhibitor which binds to the active site of the phosphatase enzyme is vanadate. Within the active site, vanadate forms a

Toward inhibitors with increased efficacy on intracellular PTP1B and of benefit in type 2 diabetes mellitus and obesity control

The ideal inhibitor should possess the ability to cross the cell membrane, to recognize distinctively cytoplasmic PTP1B, bind it with high affinity, and block the phosphatase reaction as well as the subsequent steps in the insulin or leptin signaling pathway. A strategy towards more membrane permeable PTP1B inhibitors is to enhance their hydrophobic character by the insertion of a lipophilic phenylimino moiety [30]. Another strategy consists in synthesis of ester derivatives of inhibitors which

Emerging approaches

As inhibition of PTP1B enzyme activity is of promise for alleviating insulin and leptin resistance, studies on PTP1B inhibitors are worthwhile. From the examination of the last 3 years data, several approaches appear as valuable in the near future: (i) identification of novel pro-drug delivery inhibitors, (ii) design of efficient drug-like PTP1B inhibitors, able to interact both with the catalytic as well as the secondary binding pockets of PTP1B molecule, (iii) discovery of inhibitors to be

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