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DPP4: A Multifunctional Enzyme Drug-Target for Diabetes II
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This entry is adapted from: https://doi.org/10.3390/ph18010052

The text describes the Dipeptidyl-peptidase 4 (DPP4 or CD26) emphasizing its multi-substrate and multi-functional role. As it is an established drug target for the treatment of Diabetes type II, it refers to the approved inhibitors of the enzyme, their mechanism and mode of inhibitory action and the mechanism underneath their side effects, when it is known. It also discusses the probable usefulness of uncompetitive, non-competitive or mixed inhibitors in addition to the approved competitive or covalent bond forming inhibitors because of the multi-substrate character of the enzyme.

DPP4 enzyme inhibitors competitive inhibitors uncompetitive inhibitors non-competitive inhibitors Diabetes type II side effects allosteric site biological mechanism multi-substrate enzyme

1. DPP4 Enzyme Activity

Dipeptidyl-peptidase 4 (DPP4 or CD26) is a widely studied biomolecule involved in a variety of processes [1]. It is found on the surface of most cells, while also exists in soluble form. It acts both as a receptor and as a serine exopeptidase detaching an amino-terminal dipeptide by cleaving next to proline or alanine [2][3][4].

2. A Multi-Substrate Enzyme Involved in Multiple Biochemical Mechanisms and Pathologic Disorders

Currently, DPP4 is a drug target for the treatment of diabetes type II, because of its involvement in the hydrolysis of the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) which induce glucose-dependent insulin secretion and are related to β-cells protection and proliferation [5][6]. DPP4 inhibitors are a class of anti-diabetic drugs, first approved in 2006 [7].

Experimental data also proved the involvement of DPP4 in biochemical pathways, related to immune regulation, inflammation, signal transduction, and apoptosis [1]. Since neuropeptides, such as NPY, NYY, and substance P, are among their substrates, DPP4 activity may affect their function in CNS and peripheral tissues. NPY, known for its anxiolytic activity [8], has been related to the regulation of energy balance, memory, and learning, and low levels of this neuropeptide are found in patients with depression [9]. Therefore, DPP4 could be a possible therapeutic target for depression, anxiety, and mental disorders, as well [9][10].

In addition, DPP4 expression and activity have been related to cancer development with controversial results. CD26+ cancer stem cells have been found and the role of DPP4 in the development of metastases has been highlighted. Altered DPP4 activity has been correlated with numerous tumors [11] and administration of approved DPP4 inhibitors to experimental animals appeared to limit colon cancer or lung metastasis [12]. However, other studies indicated a probable role of DPP4 inhibitors in cancer progression, proposing malignancies as one of the undesired side effects of DPP4 inhibitors [13][14][15][16].

The multiplicity of natural substrates of DPP4, with 40 different molecules found till now [17][18][19][20][21][22][23][24][25][26] may explain the involvement of DPP4 in multiple pathways and the variety of side effects. The effect of DPP4 on its substrates may result in an inactive product but may also lead to an alteration in the activity, specificity, and half-life of the initial substrate [27][28][29], sometimes leading to a more specific, more stable product [29].

3. DPP4 Inhibitors in the Treatment of Diabetes Type II

3.1. Effectivity and Side Effects

DPP4 inhibitors such as sitagliptin, saxagliptin, alogliptin, vildagliptin etc. generally known as gliptins, are currently used in the treatment of Diabetes type II. They are mostly administrated in combination with metformin with good results.

Although a number of DPP4 inhibitors have been approved and have been in use for the treatment of Diabetes type II, for over a decade, the research for finding novel potent DPP4 inhibitors continues mainly because of the accumulated data concerning the side effects and the need for safer members of this drug class. Among the ten most frequent side effects of DPP4 inhibitors are gastrointestinal nonspecific inflammation, hypersensitivity, acute pancreatitis, haemodynamic oedema, malignancies, angioedema, embolic/thrombotic events, hepatic disorders, and cardiac failure [30]. Most toxicity effects of approved DPP-4 inhibitors are attributed to abnormal increases in their substrates probably due to the increased/prolonged activity of the inhibitors at the local or general level [31][32].

An increase in the concentration of the DPP4 substrates GLP-1, GIP (also called Gastric Inhibitory Polypeptide), the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and oxyntomoduline has been related to gastrointestinal disorders [30][33]. The side effects are believed to be due to the gastrointestinal actions of the peptides apart from their Insulinotropic activity.

Acute pancreatitis, a rare but severe side effect of DPP4 inhibitors, was associated with increased activity of GLP-1, which can cause ductal hyperplasia in the pancreas with outflow obstruction leading to intrapancreatic activation of pancreatic enzymes [31][34].

The mechanism proposed for increased incidences of cardiac failure hospitalization was related to elevated concentration of the DPP4 substrates, substance P and Neuropeptide Y, both of which increase heart rate by increasing sympathetic activity. The incidences were reduced by the concomitant administration of B-blockers or ACE inhibitors which reduce blood pressure [32].

Interestingly, DPP4 inhibitors such as sitagliptin and alogliptin which are mainly excreted in the urine in their initial, unmodified form were not associated with this side effect. The inhibitors decrease the action of the sodium-hydrogen exchanger 3 (NHE3), involved in sodium reabsorption, thus decreasing blood sodium levels and blood pressure. NHE3 activity is related to DPP4 with which it forms complex, while increased expression of the exchanger is related to diabetes and heart failure [32].

The increase in substance P levels can also explain Myalgia, by its effect on the pain threshold [30].

On the other hand, an increase in inflammation mainly of the respiratory and urinary tract is related to the direct effect of the enzyme in T lymphocyte regulation and the suppression of mitogen-stimulated T-cell responses by DPP-4 inhibitors [30].

It is obvious that there is a drug-class-related organ-specific toxicity, although differences between specific drugs exist mainly attributed to differences in drug kinetics [32].

3.2. Mode of Inhibitory Action and Structural Characteristics of Approved DPP4 Inhibitors

Currently approved DPP4 drugs bind at the active site of the enzyme acting as competitive inhibitors (sitagliptin, alogliptin) or form covalent bonds with the catalytic amino acid which leads to prolonged inhibition (saxagliptin, vildagliptin) [35][36].

Structurally, the known DPP4 inhibitors are molecules rich in N atoms, containing at least one CO group bound to N, in a peptide bond mimicking effort. Aromatic and hydrophobic groups, among which phenyl (e.g., sitagliptin, alogliptin) and adamantane (e.g., saxagliptin, vildagliptin) moieties are present in the structures. Fluorine atoms, mostly in the form of F-substituents of phenyl rings or -CF3 groups, are present in several approved inhibitors such as sitagliptin, gemigliptin, and evogliptin.

3.3. Reasoning for the Efficacy of Different Types of Inhibitors in the Treatment of Diabetes

Competitive inhibitors have reversible activity, exhibiting increased inhibition at lower substrate concentrations and low to no efficiency at relatively high substrate concentrations, which may be present at a tissue level under specific circumstances. In the case of enzymes with multiple substrates, the high cumulative concentration of different substrates may be observed locally, especially if the substrates are products of the same precursor-protein, they are co-secreted or one acts as a secretion enhancer of the other and they are increased simultaneously in response to the same stimuli. These kinds of interactions occur in the group of DPP4 insulinotropic substrates [37][38]. At the same time, abnormal increase of other enzyme substrates, secreted at low concentrations at distant locations can be observed. On the other hand, covalent bond-forming inhibitors may cause prolonged inhibition which could also lead to abnormal increase in DPP4 substrates with probable side effects [37].

As an enzyme with a crucial role in several mechanisms, the action of DPP4 must be under strict control by factors some of which may be unknown till now, and allosteric sites for the binding of natural inhibitors or enhancers are expected to be revealed.

Inhibitors with non-covalent, reversible binding to allosteric sites could cause more balanced inhibition at a wide range of substrate concentrations. Moreover, the discovery of such inhibitors may constitute the first step for finding allosteric sites of the enzyme and better exploring its role and interactions. Till now, a very limited number of studies refer to such inhibitors [37][39][40][41][42][43][44][45][46]. The existence of uncompetitive and non-competitive inhibitors indicates the presence of allosteric sites.

This site can be within the cavity of the active site or can be outside the cavity at a neighboring or remote location. There are many examples in which the allosteric site is placed at a remarkable distance. In the case of DPP4, a phenomenon of remote control of enzyme activity has been mentioned concerning mutations of amino acids at positions far away from the active site with no obvious implication in catalysis. Despite the distance, the mutations affect the Κm and Vmax of the enzyme. Such mutations are T351A, K554Q, R492K, V486M, D65E, and A291P, with V486M which leads to inactivation, being the most remote one [47]. This indicates that in this enzyme, an effect at a site at a great distance from the catalytic triad may cause inhibition and the sites of inhibiting mutations may be such sites.

An effort to predict the probable position of the allosteric site was conducted using the results of the docking analysis of the whole enzyme.

Figure 1. Active site of DPP4 (a) and probable sites of binding of uncompetitive (sites a1, b) and non-competitive (site a2) inhibitors, according to docking analysis using the DPP4 structure 2OAG [37].

Although crystallographic studies are needed to reveal these sites, an effort using Docking analysis was performed, indicating one probable site (a2) for non-competitive inhibitor at the wider area of the active center and two probable site of binding for uncompetitive inhibitors, one at the wider area of the active site cavity (a1) and one at the area of propeller loop (b) [37]. However, binding at this site is restricted. DPP4 forms a dimer with the propeller loop taking part in dimer formation. DPP4 dimers are not in equilibrium with monomers and dimerization is necessary for catalytic activity [47][48]. Interestingly, during catalysis, the propeller loop moves several times between a “closed” and an “open” pose, and this movement is considered as essential for the catalytic procedure. Preventing propeller loop movement in V486M mutation leads to the inactivation of the enzyme [48]. It is not known if the conformations adapted during the movement of the loop enable the binding of the inhibitors [37].

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Phaedra Eleftheriou
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