Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large for inhibition by small molecules, and inaccessible to larger biologics. In the past two decades, evidence associating the misfolding and aggregation of alpha-synuclein strongly implicates this protein in disease onset and progression of Parkinson’s disease and related synucleinopathies. The subsequent formation of toxic, intracellular, Lewy body deposits, in which alpha-synuclein is a major component, is a key diagnostic hallmark of the disease. To reach their therapeutic site of action, peptides must both cross the blood-brain barrier and enter dopaminergic neurons to prevent the formation of these intracellular inclusions. In this review, we describe and summarise the current efforts made in the development of peptides and their mimetics to directly engage with alpha-synuclein with the intention of modulating aggregation, and importantly, toxicity. This is a rapidly expanding field with great socioeconomic impact; these molecules harbour significant promise as therapeutics, or as early biomarkers during prodromal disease stages, or both. As these are age-dependent conditions, an increasing global life expectancy means disease prevalence is rising. No current treatments exist to either prevent or slow disease progression. It is therefore crucial that drugs are developed for these conditions before health care and social care capacities become overrun.

中文翻译：

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基于肽的方法直接靶向帕金森病的α-突触核蛋白

肽及其模拟物越来越多地被认为是类药物分子，特别是对于小分子难以抑制的细胞内蛋白质-蛋白质相互作用而言，并且较大的生物制剂无法接近。在过去的二十年中，有证据表明α-突触核蛋白的错误折叠和聚集与帕金森病和相关突触核蛋白病的发病和进展密切相关。随后形成有毒的细胞内路易体沉积物（其中α-突触核蛋白是主要成分），是该疾病的关键诊断标志。为了到达其治疗作用位点，肽必须穿过血脑屏障并进入多巴胺能神经元，以防止这些细胞内包涵体的形成。在这篇综述中，我们描述并总结了目前在开发肽及其模拟物方面所做的努力，以直接与α-突触核蛋白结合，以调节聚集，并且重要的是调节毒性。这是一个快速发展的领域，具有巨大的社会经济影响；这些分子作为治疗药物或作为前驱疾病阶段的早期生物标志物，或两者兼而有之。由于这些疾病与年龄有关，全球预期寿命的延长意味着疾病患病率正在上升。目前尚无治疗方法可以预防或减缓疾病进展。因此，在医疗保健和社会保健能力超支之前开发针对这些疾病的药物至关重要。