Arginase Inhibitors: A Rational Approach Over One Century

Abstract

Arginase (EC 3.5.3.1) is the bimanganese enzyme that converts L-arginine into ornithine and urea. This enzyme was discovered more than a century ago and early α-amino acids were identified as weak inhibitors. It was only during the 90s, after nitric oxide (NO) was reported as one of the most important biological mediators and when tight interrelation of arginase and NO synthase was found, that the development of arginase inhibitors was accelerated. The regulation of arginase activity by the N-hydroxy-L-arginine (3, NOHA) intermediate of the NO synthesis was the starting point of the N-hydroxy-nor-arginine (21, nor-NOHA) that proved to be the first micromolar inhibitor. The previously known manganese and arginase binding by borate inspired the 2(S)-amino-6-boronohexanoic acid (39, ABH) and S-(2-boronoethyl)-L-cysteine (40, BEC) now both considered as reference compounds in arginase inhibition. The high-resolution crystal structure of arginase and molecular modeling has rendered possible the recent design of (53) the strongest α,α-disubstituted derivatives of ABH. Simultaneously, traditional medicinal plants have contributed as a source of molecular diversity to the discovery of arginase inhibitors. This rational, step-by-step approach serves as guide in the present review where emphasis is placed on structure activity relationships. Highlights exhaustive review on arginase inhibitors highlight is made on rational approach to conception and structure activity relationships evaluation model is systematically mentioned with results.

Targeting the arginine metabolic brake enhances immunotherapy for leukaemia

“…A more direct approach to metabolic modulating therapy would be to target the Arginase II enzyme's active site. A multitude of novel inhibitors have sought to target arginase enzymes, mostly with limitations such as reversibility, a failure to cross the cell membrane, or the need to block both Arginase and INOS enzymes if present in cancer cells . The most clinically advanced arginase inhibitor is CB‐1158 (Calithera), an orally active agent that is undergoing clinical trial alongside checkpoint inhibitors in patients with advanced solid tumours (NCT02903914).…”

NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence

“…The hydrogen peroxide or l -NAME-induced increases in cellular senescence were blocked by co-treatment of the cultures with the arginase inhibitor ABH or the NO donor SNAP (Figure 9 and Figure 10), suggesting a mechanism involving arginase-induced decreases in NO bioavailability. ABH is highly specific for arginase activity; it inhibits both arginase isoforms and does not alter NOS activity [29,30]. …”

“…After 2 h, the cultures were switched to 25 mM glucose (HG) or 5 mM glucose (NG) media along gp91ds-tat or SC peptide and maintained for 72 h. Other cultures were treated with H 2 O 2 (5, 15, 25, 50 µM, Sigma-Aldrich, St. Louis, MO, USA) for different times. To assess the contribution of arginase activity, some cultures were treated with or without the arginase inhibitor ABH (2(S)-amino-6-boronohexanoic acid, 100 µM) [29,30]. The involvement of NOS activity was evaluated by treating other cultures with or without l -NAME ( l -NG-nitroarginine methyl ester, 100 µM, Sigma-Aldrich, St. Louis, MO, USA) and/or the NO donor SNAP (S-nitroso-N-acetyl-D, l -penicillamine, 10 µM, Sigma-Aldrich, St. Louis, MO, USA).…”

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“…This is due to the fact that the synthesis of proline and polyamines could be blocked, as well as the possibility of a possible disruption of the urea cycle in the liver. It seems contradictory that studies regarding ARG inhibition do not report significant toxic effects on the urea cycle, possibly because of high levels of ARG expression in the liver (up to one thousand times more than normal) compared to the endothelium, therefore making it unlikely that the suppression of this function can be achieved by therapeutically viable doses of the inhibitor [6,124]. From another point of view, human ARG deficiency seems to be a disorder that is effectively treated, and acute hyperammonaemia does not represent a great risk for most patients [123].…”