Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
Br J Pharmacol. 2021 Mar;178(5):1095-1113. doi: 10.1111/bph.15344. Epub 2021 Jan 26.
Excessive oxidative stress can induce PARP1-mediated programmed necrotic cell death, termed parthanatos. Inhibition of parthanatos may be therapeutically beneficial in a wide array of diseases associated with tissue injury and inflammation. Our goal was to identify novel molecules inhibiting parthanatos.
A small library of 774 pharmacologically active compounds was screened in a Sytox Green uptake assay, which identified 20 hits that reduced hydrogen-peroxide-induced parthanatos with an efficiency comparable to the benchmark PARP inhibitor, PJ34.
Of these hits, two compounds, antifungal ciclopirox and dopamine receptor agonist apomorphine, inhibited PAR polymer synthesis. These two compounds prevented the binding of PARP1 to oxidatively damaged DNA but did not directly interfere with the interaction between DNA and PARP1. Both compounds inhibited mitochondrial superoxide and H O production and suppressed DNA breakage. Since H O -induced damage is dependent on Fe -catalysed hydroxyl radical production (Fenton chemistry), we determined the iron chelation activity of the two test compounds and found that ciclopirox and, to a lesser extent, apomorphine act as iron chelators. We also show that the Fe chelation and indirect PARP inhibitory effects of ciclopirox translate to anti-inflammatory actions as demonstrated in a mouse dermatitis model, where ciclopirox reduced ear swelling, inflammatory cell recruitment and poly(ADP-ribosyl)ation.
Our findings indicate that the antimycotic drug, ciclopirox, acts as an iron chelator and thus targets an early event in hydrogen-peroxide-induced parthanatos. Ciclopirox has the potential to be repurposed as a cytoprotective and anti-inflammatory agent.
过度的氧化应激会诱导 PARP1 介导的程序性坏死细胞死亡，称为 PARthanatos。PARthanatos 的抑制可能在与组织损伤和炎症相关的广泛疾病中具有治疗益处。我们的目标是确定抑制 PARthanatos 的新型分子。
用 Sytox Green 摄取测定法筛选了 774 种具有药理活性的化合物的小文库，该测定法确定了 20 个可降低过氧化氢诱导的 PARthanatos的化合物，其效率与基准 PARP 抑制剂 PJ34 相当。
在这些命中物中，两种化合物，抗真菌环吡酮和多巴胺受体激动剂阿朴吗啡，抑制了 PAR 聚合酶的合成。这两种化合物阻止了 PARP1 与氧化损伤 DNA 的结合，但没有直接干扰 DNA 与 PARP1 的相互作用。两种化合物均抑制线粒体超氧化物和 H2O2 的产生，并抑制 DNA 断裂。由于 H2O2 诱导的损伤依赖于 Fe 催化的羟基自由基产生（Fenton 化学），我们确定了两种测试化合物的铁螯合活性，发现环吡酮和在较小程度上阿朴吗啡作为铁螯合剂。我们还表明，环吡酮的铁螯合和间接 PARP 抑制作用转化为抗炎作用，如在小鼠皮炎模型中所示，其中环吡酮减少了耳肿胀、炎症细胞募集和聚（ADP-核糖基）化。
我们的研究结果表明，抗真菌药物环吡酮作为铁螯合剂起作用，从而靶向过氧化氢诱导的 PARthanatos 的早期事件。环吡酮有可能被重新用作细胞保护和抗炎剂。
