Department of Life Sciences, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Mol Neurodegener. 2023 Nov 9;18(1):80. doi: 10.1186/s13024-023-00675-8.
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.
肽及其类似物越来越被认为是具有药物特性的分子，特别是对于太大而无法被小分子抑制的细胞内蛋白质-蛋白质相互作用，以及无法被更大的生物制剂治疗的靶点。在过去的二十年中，与α-突触核蛋白错误折叠和聚集相关的证据强烈表明该蛋白与帕金森病和相关的突触核蛋白病的发病和进展有关。随后形成的有毒的、细胞内的路易体沉积物中，α-突触核蛋白是主要成分，这是该疾病的一个关键诊断标志。为了到达其治疗作用部位，肽必须既能穿过血脑屏障，又能进入多巴胺能神经元，以防止这些细胞内包含物的形成。在这篇综述中，我们描述并总结了目前在开发肽及其类似物方面所做的努力，这些肽及其类似物旨在直接与α-突触核蛋白结合，以调节其聚集，更重要的是，调节其毒性。这是一个快速发展的领域，具有巨大的社会经济影响；这些分子作为治疗剂具有很大的潜力，或者作为疾病前驱期的早期生物标志物，或者两者兼而有之。由于这些都是与年龄相关的疾病，全球预期寿命的增加意味着疾病的流行率正在上升。目前没有治疗方法可以预防或减缓疾病的进展。因此，在医疗保健和社会保健能力不堪重负之前，为这些疾病开发药物至关重要。
