Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described in organisms allover the phylogenetic tree. They catalyze the hydration of CO2 to bicarbonate and protons, and are involved in pH regulation, chemosensing and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension and recently, as antitumor theragnostic agents. Other potential applications include the use of CA inhibitors (CAIs) in inflammatory conditions, cerebral ischemia, neuropathic pain, or for Alzheimer's/Parkinson's disease management. CAs from pathogenic bacteria, fungi, protozoans and nematodes started to be considered as drug targets in recent years, with notable advances registered ultimately. CAIs have a complex multipharmacology probably unique to this enzyme, which has been exploited intensely but may lead to other relevant applications in the future, due to the emergence of drug design approaches which afforded highly isoform-selective compounds for most α-CAs known to date. They belong to a multitude of chemical classes (sulfonamides and isosteres, (iso)coumarins and related compounds, mono- and dithiocarbamates, selenols, ninhydrines, boronic acids, benzoxaboroles, etc). The polypharmacology of CAIs will also be discussed since drugs originally discovered for the treatment of non-CA related conditions (topiramate, zonisamide, celecoxib, pazopanib, thiazide and high-ceiling diuretics) show efective inhibition against many CAs, which led to their repurposing for diverse pharmacological applications. Significance Statement Carbonic anhydrase inhibitors have multiple pharmacologic applications as diuretics, antiglaucoma, antiepileptic, antiobesity, anti-acute mountain sickness, anti-idiopathic intracranial hypertension and as antitumor drugs. Their use in inflammatory conditions, cerebral ischemia, neuropathic pain, or neurodegenerations started to be investigated recently. Parasite carbonic anhydrases are also drug targets for antiinfectives with novel mechanisms of action which can by pass drug resistance to commonly used such agents. Drugs discovered for the management of other conditions that effectively inhibit these enzymes exert interesting polypharmacologic effects.

中文翻译：

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碳酸酐酶抑制剂的多药理学。


在整个系统发育树的生物体中描述了八个遗传上不同的碳酸酐酶家族（CA，EC 4.2.1.1）。它们催化二氧化碳水合为碳酸氢盐和质子，并参与 pH 调节、化学传感和代谢。人类体内存在的 15 种 α-CA 亚型是几十年来已知的药理学药物靶标，它们的抑制剂被用作利尿剂、抗青光眼、抗癫痫或抗肥胖药物，以及用于治疗急性高山病、特发性颅内高压，最近还用作抗肿瘤药物治疗诊断剂。其他潜在的应用包括在炎症、脑缺血、神经性疼痛或阿尔茨海默病/帕金森病治疗中使用 CA 抑制剂 (CAI)。近年来，来自病原细菌、真菌、原生动物和线虫的 CA 开始被视为药物靶点，并最终取得了显着进展。 CAI 具有复杂的多药理学，可能是这种酶独有的，它已被广泛开发，但由于药物设计方法的出现，为迄今为止已知的大多数 α-CA 提供了高度异构体选择性的化合物，因此未来可能会导致其他相关应用。它们属于多种化学类别（磺酰胺和电子等排物、（异）香豆素和相关化合物、单硫代氨基甲酸酯和二硫代氨基甲酸酯、硒醇、茚三酮、硼酸、苯并氧硼杂环等）。还将讨论 CAIs 的多药理学，因为最初发现的用于治疗非 CA 相关病症的药物（托吡酯、唑尼沙胺、塞来昔布、帕唑帕尼、噻嗪类和高天花板利尿剂）对许多 CA 表现出有效的抑制作用，这导致它们重新用于治疗多样化的药理应用。 意义陈述 碳酸酐酶抑制剂具有多种药理学应用，如利尿剂、抗青光眼、抗癫痫、抗肥胖、抗急性高山病、抗特发性颅内高压和抗肿瘤药物。最近开始研究它们在炎症、脑缺血、神经性疼痛或神经变性中的应用。寄生虫碳酸酐酶也是具有新颖作用机制的抗感染药的药物靶点，可以绕过对常用此类药物的耐药性。为治疗其他病症而发现的可有效抑制这些酶的药物发挥了有趣的多药理作用。