Synthesis and Evaluation of a Mitochondria-Targeting Poly(ADP-ribose) Polymerase-1 Inhibitor,ACS Chemical Biology

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Synthesis and Evaluation of a Mitochondria-Targeting Poly(ADP-ribose) Polymerase-1 Inhibitor
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-09-05 00:00:00 , DOI: 10.1021/acschembio.8b00423
Tanja Krainz ₁ , Andrew M. Lamade ₂ , Lina Du ₂ , Taber S. Maskrey ₁ , Michael J. Calderon ₃ , Simon C. Watkins ₃ , Michael W. Epperly ₄ , Joel S. Greenberger ₄ , Hülya Bayır _{2,

5,

6} , Peter Wipf ₁ , Robert S. B. Clark _{2,

6}

Affiliation

The poly(ADP-ribose) polymerase (PARP) family of enzymes plays a crucial role in cellular and molecular processes including DNA damage detection and repair and transcription; indeed, PARP inhibitors are under clinical evaluation as chemotherapeutic adjuncts given their capacity to impede genomic DNA repair in tumor cells. Conversely, overactivation of PARP can lead to NAD⁺ depletion, mitochondrial energy failure, and cell death. Since PARP activation facilitates genomic but impedes mitochondrial DNA repair, nonselective PARP inhibitors are likely to have opposing effects in these cellular compartments. Herein, we describe the synthesis and evaluation of the mitochondria-targeting PARP inhibitor, XJB-veliparib. Attachment of the hemigramicidin S pentapeptide isostere for mitochondrial targeting using a flexible linker at the primary amide site of veliparib did not disrupt PARP affinity or inhibition. XJB-veliparib was effective at low nanomolar concentrations (10–100 nM) and more potent than veliparib in protection from oxygen-glucose deprivation (OGD) in primary cortical neurons. Both XJB-veliparib and veliparib (10 nM) preserved mitochondrial NAD⁺ after OGD; however, only XJB-veliparib prevented release of NAD⁺ into cytosol. XJB-veliparib (10 nM) appeared to inhibit poly(ADP-ribose) polymer formation in mitochondria and preserve mitochondrial cytoarchitecture after OGD in primary cortical neurons. After 10 nM exposure, XJB-veliparib was detected by LC-MS in mitochondria but not nuclear-enriched fractions in neurons and was observed in mitoplasts stripped of the outer mitochondrial membrane obtained from HT22 cells. XJB-veliparib was also effective at preventing glutamate-induced HT22 cell death at micromolar concentrations. Importantly, in HT22 cells exposed to H₂O₂ to produce DNA damage, XJB-veliparib (10 μM) had no effect on nuclear DNA repair, in contrast to veliparib (10 μM) where DNA repair was retarded. XJB-veliparib and analogous mitochondria-targeting PARP inhibitors warrant further evaluation in vitro and in vivo, particularly in conditions where PARP overactivation leads to mitochondrial energy failure and maintenance of genomic DNA integrity is desirable, e.g., ischemia, oxidative stress, and radiation exposure.

中文翻译：

线粒体靶向聚（ADP-核糖）聚合酶-1抑制剂的合成和评价。

聚（ADP-核糖）聚合酶（PARP）酶家族在细胞和分子过程中起着至关重要的作用，包括DNA损伤的检测，修复和转录。实际上，鉴于PARP抑制剂具有阻止肿瘤细胞中基因组DNA修复的能力，因此正在作为一种化学治疗辅助剂进行临床评估。相反，PARP过度激活会导致NAD ⁺耗竭，线粒体能量衰竭和细胞死亡。由于PARP激活有助于基因组学但阻碍线粒体DNA修复，因此非选择性PARP抑制剂可能在这些细胞区室中具有相反的作用。在本文中，我们描述了靶向线粒体的PARP抑制剂XJB-veliparib的合成和评估。使用柔性接头在veliparib的主要酰胺位点连接半角蛋白S五肽等排体用于线粒体靶向，不会破坏PARP亲和力或抑制作用。XJB-veliparib在低纳摩尔浓度（10-100 nM）时有效，并且在保护原代皮层神经元免受氧-葡萄糖剥夺（OGD）方面比veliparib更有效。XJB-veliparib和veliparib（10 nM）均可保存线粒体NAD ⁺OGD之后；但是，只有XJB-veliparib可以阻止NAD ⁺释放到细胞质中。XJB-veliparib（10 nM）似乎抑制原代皮层神经元发生OGD后线粒体中的聚（ADP-核糖）聚合物形成并保留线粒体的细胞结构。暴露10 nM后，通过LC-MS在线粒体中检测到XJB-veliparib，但在神经元中未检测到核富集级分，并且在从HT22细胞获得的剥脱线粒体外膜的原生质体中观察到了XJB-veliparib。XJB-veliparib在微摩尔浓度下也能有效防止谷氨酸诱导的HT22细胞死亡。重要的是，在暴露于H ₂ O _2的HT22细胞中为了产生DNA损伤，XJB-veliparib（10μM）对核DNA的修复没有影响，而veliparib（10μM）则使DNA的修复受到阻碍。XJB-veliparib和类似线粒体靶向PARP抑制剂需要进一步评估在体外和在体内，尤其是在条件，其中PARP过度激活导致线粒体能量故障和维护的基因组DNA完整性的是理想的，例如，局部缺血，氧化应激和辐射暴露。

更新日期：2018-09-05

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