Misfolded prion protein (PrP^Sc) is known for its role in fatal neurodegenerative conditions, such as Creutzfeldt–Jakob disease. PrP fragments and their mutants represent important tools in the investigation of the neurotoxic mechanisms and in the evaluation of new compounds that can interfere with the processes involved in neuronal death. Metal-catalyzed oxidation of PrP has been implicated as a trigger for the conformational changes in protein structure, which, in turn, lead to misfolding. Targeting redox-active biometals copper and iron is relevant in the context of protection against the oxidation of biomolecules and the generation of oxidative stress, observed in several conditions and considered an event that might promote sporadic prion diseases as well as other neurodegenerative disorders. In this context, ortho-pyridine aroylhydrazones are of interest, as they can act as moderate tridentate ligands towards divalent metal ions such as copper(II). In the present work, we explore the potentiality of this chemical class as peptide protecting agents against the deleterious metal-catalyzed oxidation in the M112A mutant fragment of human PrP, which mimics relevant structural features that may play an important role in the neurotoxicity observed in prion pathologies. The compounds inhere studied, especially HPCFur, showed an improved stability in aqueous solution compared to our patented lead hydrazone INHHQ, displaying a very interesting protective effect toward the oxidation of methionine and histidine, processes that are related to both physiological and pathological aging.

中文翻译：

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吡啶-2-羧醛衍生的芳酰hydr对铜催化的M112A PrP103-112突变片段的氧化的影响。

错折叠的病毒蛋白（PrP ^Sc）以其在致命的神经退行性疾病（例如克雅氏病）中的作用而著称。PrP片段及其突变体是研究神经毒性机制和评估可能干扰神经元死亡过程的新化合物的重要工具。PrP的金属催化氧化被认为是蛋白质结构构象变化的触发因素，进而导致错误折叠。针对氧化还原活性的生物金属铜和铁在防止生物分子氧化和氧化应激的产生方面具有重要意义，在几种情况下均已观察到该现象，并认为该事件可能会导致散发性ion病毒疾病以及其他神经退行性疾病。在这种情况下，邻吡啶吡啶芳酰基hydr是令人感兴趣的，因为它们可以充当二价金属离子（如铜（II））的中等三齿配体。在目前的工作中，我们探索这种化学类别作为肽保护剂抵抗人类PrP的M112A突变片段中有害金属催化的氧化的潜力，其模仿了可能在in病毒中观察到的神经毒性中起重要作用的相关结构特征。病理。与我们的专利lead铅INHHQ相比，本文研究的化合物（尤其是HPCFur）在水溶液中显示出更高的稳定性，对蛋氨酸和组氨酸的氧化表现出非常有趣的保护作用，该过程与生理和病理学衰老相关。