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International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors
Pharmacological Reviews ( IF 19.3 ) Pub Date : 2017-10-01 , DOI: 10.1124/pr.117.014050
Csaba Szabo 1 , Andreas Papapetropoulos 1
Affiliation  

Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition of H2S biosynthesis. H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasing H2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, an H2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.

中文翻译:


国际基础与临床药理学联盟。 CII:H2S 水平的药理学调节:H2S 供体和 H2S 生物合成抑制剂



在过去的十年中,硫化氢(H 2 S)已成为哺乳动物细胞和组织中重要的内源性气体递质。与之前表征的气体递质一氧化氮和一氧化碳类似,H 2 S 由各种酶促反应产生,并调节各种细胞和组织中的许多生理和病理生理过程。 H 2 S水平在多种情况下(例如,糖尿病、缺血和衰老)降低,而在其他情况下(例如,炎症、危重疾病和癌症)升高。在过去的几十年中,已经确定了多种用于 H 2 S 治疗利用的方法,或者基于 H 2 S 捐赠,或者基于 H 2 S 生物合成的抑制。 H 2 S供给可以通过吸入H 2 S气体和/或所谓的快速释放H 2 S供给体(H 2 S的盐,例如NaHS和Na 2 S)或慢速释放的H 2 S供给体的胃肠外或肠内施用来实现。 -释放H 2 S供体(GYY4137是数百项体外和体内研究中使用的原型化合物)。最近的工作还确定了具有受调节的 H 2 S 释放特征的各种供体,包括氧化剂触发的供体、pH 依赖性供体、酯酶激活的供体和细胞器靶向(例如线粒体)化合物。还有一些方法可以利用现有的、临床批准的各种类别的药物(例如,非甾体抗炎药)与 H 2 S 供体基团结合(临床试验中最先进的化合物是 ATB-346,非甾体抗炎化合物萘普生的 H 2 S 供体衍生物)。对于H 2 S合成的药理学抑制,现在有几种小分子化合物分别针对三种H 2 S产生酶:胱硫醚-β-合酶(CBS)、胱硫醚-γ-裂解酶和3-巯基丙酮酸硫转移酶。尽管许多这些化合物都有其局限性(效力、选择性),但这些分子,特别是与遗传方法相结合,可以有助于描述涉及内源性 H 2 S 产生的生物过程。此外,其中一些化合物(例如,CBS抑制剂氨氧乙酸盐的细胞渗透性前药,或苄丝肼,一种潜在可重新利用的CBS抑制剂)可以作为未来临床转化的起点。本文概述了目前已知的 H 2 S 供体和 H 2 S 生物合成抑制剂,描述了它们的作用模式,并提供了它们的生物效应和潜在治疗用途的示例。
更新日期:2018-02-02
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