Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
Institute for Biocomputation and Physics of Complex Systems (BIFI)-Joint Unit BIFI-IQFR (CSIC), University of Zaragoza, Zaragoza, Spain.
Nat Commun. 2021 Jun 18;12(1):3752. doi: 10.1038/s41467-021-24039-2.
α-Synuclein aggregation is a key driver of neurodegeneration in Parkinson's disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein toxic assemblies with high affinity is a long-pursued objective. Here, we exploit the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of α-helical peptides that bind to these α-synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into a high anti-aggregation potency and the ability to abrogate oligomer-induced cell damage. Using a structure-guided search we identify a human peptide expressed in the brain and the gastrointestinal tract with analogous binding, anti-aggregation, and detoxifying properties. The chemical entities we describe here may represent a therapeutic avenue for the synucleinopathies and are promising tools to assist diagnosis by discriminating between native and toxic α-synuclein species.
α-突触核蛋白聚集是帕金森病和相关综合征神经退行性变的关键驱动因素。因此，获得一种能以高亲和力靶向α-突触核蛋白毒性聚集物的分子是长期追求的目标。在这里，我们利用有毒寡聚体和淀粉样纤维的生物物理特性来鉴定一组α-螺旋肽，这些肽与这些α-突触核蛋白具有低纳摩尔亲和力的结合，而不干扰单体功能蛋白。这种活性转化为高抗聚集能力，并能消除寡聚体诱导的细胞损伤。通过结构引导搜索，我们鉴定出一种在大脑和胃肠道中表达的具有类似结合、抗聚集和解毒特性的人类肽。我们在这里描述的化学实体可能代表了一种治疗突触核蛋白病的方法，并且是通过区分天然和有毒的α-突触核蛋白来辅助诊断的有前途的工具。
