Arginase inhibitors: from chlorogenic acid to cinnamides

The interest to consider arginase, a metalloenzyme hydrolysing L-arginine to L-ornithine and urea, as a therapeutic target has grown in the recent years and the use of arginase inhibitors has been proved to be beneficial in cardiovascular and nervous system diseases [1]. However, the most potent commercial inhibitors cannot be used in clinic due to their pharmacokinetic and toxicological properties [2]. Search for new inhibitors is thus required and such compounds may be inspired by natural substances [3]. Further to a screening of a series of natural polyphenols on an arginase inhibitory assay using purified liver bovine arginase (b-ARG I), we showed that chlorogenic acid could serve as a lead compound to design new arginase inhibitors [4]. In particular, our findings suggested that the caffeoyl moiety could be crucial for arginase inhibition. In the present study, we focused on development of chlorogenic acid derivatives wherein the quinoyl moiety was replaced by a phenethylamine. A series of cinnamide derivatives was thus synthesized and evaluated for their in vitro inhibitory activity on b-ARG I. Moreover, a homology structure of b-ARG I was created and used for molecular docking to predict the interaction of cinnamides toward the active site of the enzyme. Our results showed that caffeic acid phenethyl amide (CAPA) was the most potent inhibitor (IC₅₀ value 6.9 ± 1.3µM), still weaker than the reference inhibitor nor-NOHA (IC₅₀ value 1.7 ± 0.2µM) but slightly more active than chlorogenic acid (IC₅₀ value 10.6 ± 0.8µM). Structure-activity relationship showed that cinnamoyl moiety and catechol function were important for inhibitory activity. Docking results demonstrated that caffeoyl moiety could penetrate into the active-site pocket whereas catechol and amide groups might interact with several crucial residues involved in the hydrolysis mechanism of enzyme. This study suggests that 3,4-dihydroxycinnamides could be considered as potential arginase inhibitors.

Acknowledgements: The Ministère Français de l'Enseignement supérieur et de la Recherche for awarding a PhD fellowship to T.-N. Pham. The molecular modeling work was supported by the Vietnam's National Foundation for Science and Technology Development – NAFOSTED (Grant # 106-YS. 05 – 2015.31 to Khac-Minh Thai). Andy Zedet is acknowledged for technical assistance.

Keywords: liver bovine arginase, inhibitors, polyphenols, docking study, cinnamides.

References:

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[2] Ivanenkov YA, Chufarova NV. Small-molecule arginase inhibitors. Pharm Pat Anal 2013; 3: 65 – 85

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[4] Pham TN, Guglielmetti AS, Fimbel S, Demougeot C, Girard-Thernier C. Arginase inhibitory activity of several natural polyphenols using a novel in vitro test on purified arginase. Planta Med 2014; 80: P1L9