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：

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国际基础和临床药理学联盟。CII：H2S水平的药理调节：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一种重要的内源性气体递质。与先前表征的气体递质一氧化氮和一氧化碳相似，H ₂ S通过各种酶促反应产生，并调节各种细胞和组织中的许多生理和病理生理过程。在许多情况下（例如，糖尿病，局部缺血和衰老），H ₂ S水平降低，而在其他状态（例如，炎症，危重疾病和癌症）下，H ₂ S水平升高。在过去的几十年中，基于捐献H ₂ S或抑制H ₂，已鉴定出多种治疗H ₂ S的方法。₂ S生物合成。H ₂ S的捐赠可以通过吸入H ₂ S气体和/或肠胃外或肠内施用所谓的速释H ₂ S供体（H ₂ S的盐，例如NaHS和Na ₂ S）或缓慢地进行释放H ₂ S供体（GYY4137是在体外和体内数百项研究中使用的原型化合物）。最近的工作还确定了各种受管制的H ₂捐助者S释放曲线，包括氧化剂触发的供体，pH依赖性供体，酯酶激活的供体和靶向细胞器的（例如线粒体）化合物。在某些方法中，现有的各种类型的临床批准药物（例如，非甾体类抗炎药）与H ₂ S捐赠基团结合（临床试验中最先进的化合物是A ₂ H捐赠衍生物ATB-346）非甾体类抗炎化合物萘普生）。为了抑制H ₂ S合成的药理作用，现在有几种针对三种产生H ₂ S的酶胱硫醚-β-合酶（CBS），胱硫醚-γ的小分子化合物-裂解酶和3-巯基丙酮酸硫转移酶。尽管这些化合物中的许多都有其局限性（效力，选择性），但这些分子（尤其是与遗传方法结合使用的分子）可有助于描述涉及内源性H ₂ S产生的生物过程。此外，这些化合物中的某些（例如，CBS抑制剂氨氧基乙酸的细胞可渗透前药，或苄丝肼，一种潜在的可重复利用的CBS抑制剂）可作为未来临床翻译的起点。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，描述了它们的作用方式，并提供了其生物学作用和潜在治疗作用的实例。