Girard-Thernier C, Pham T-N, Demougeot C
EA 4267 "Fonctions et Dysfonctions Epitheliales", Universite de Franche-Comte, UFR Sciences Medicales et Pharmaceutiques, 19 rue Ambroise Pare, batiment S, 25030 BESANCON cedex, France.
Mini Rev Med Chem. 2015;15(10):798-808. doi: 10.2174/1389557515666150511153852.
The enzyme arginase catalyses the divalent cation dependent hydrolysis of L-arginine to produce L-ornithine and urea. Two isoforms of arginases have been identified in mammalian (including human) cells. Moreover, some infectious pathogens (e.g. Leishmania) synthesize their own arginase. Work over the last decades has revealed that elevated arginase activity both decreases cellular availability in nitric oxide (NO) by competing with NO synthases (NOS) and increases concentration in L-ornithine, a precursor in the biosynthesis of polyamines which are important for cell differentiation and proliferation. From these data emerged the concept that selective arginase inhibitors might be a valuable strategy for treatment of various diseases associated with decreased NO and/or increased polyamines production. Consistent with this, recent research provides compelling evidence supporting the beneficial effects of arginase inhibitors in cardiovascular diseases (hypertension, ischemia reperfusion injury, atherosclerosis, diabetes mellitus), asthma, cancer, immunologically-mediated diseases or leishmaniasis. Despite active programs to identify potent arginase inhibitors, effective chemical compounds with reliable pharmacokinetics and toxicological properties are rare. The present review summarizes available data on the discovery of new arginase inhibitors from natural origin. Current knowledge on plant-derived compounds or extracts with arginase inhibitory properties as well as available data on structure-activity relationship (SAR) will be presented. Lastly, the present review will open up new prospects in order to improve the discovery of novel arginase inhibitors from natural sources.
精氨酸酶催化L-精氨酸的二价阳离子依赖性水解，生成L-鸟氨酸和尿素。在哺乳动物（包括人类）细胞中已鉴定出两种精氨酸酶同工型。此外，一些传染性病原体（如利什曼原虫）会合成自身的精氨酸酶。过去几十年的研究表明，精氨酸酶活性升高会通过与一氧化氮合酶（NOS）竞争而降低细胞内一氧化氮（NO）的可用性，并增加L-鸟氨酸的浓度，L-鸟氨酸是多胺生物合成的前体，对细胞分化和增殖很重要。基于这些数据，提出了一种概念，即选择性精氨酸酶抑制剂可能是治疗与NO减少和/或多胺产生增加相关的各种疾病的一种有价值的策略。与此一致的是，最近的研究提供了令人信服的证据，支持精氨酸酶抑制剂在心血管疾病（高血压、缺血再灌注损伤、动脉粥样硬化、糖尿病）、哮喘、癌症、免疫介导疾病或利什曼病中的有益作用。尽管有积极的计划来鉴定有效的精氨酸酶抑制剂，但具有可靠药代动力学和毒理学特性的有效化合物却很少见。本综述总结了从天然来源发现新的精氨酸酶抑制剂的现有数据。将介绍关于具有精氨酸酶抑制特性的植物衍生化合物或提取物的现有知识以及关于构效关系（SAR）的可用数据。最后，本综述将开拓新的前景，以改进从天然来源发现新型精氨酸酶抑制剂的方法。
