High-affinity binding of celastrol to monomeric α-synuclein mitigates in vitro aggregation

α-Synuclein (αSyn) aggregation is associated with Parkinson’s disease (PD). The region αSyn_36-42 acts as the nucleation 'master controller’ and αSyn_1-12 as a ‘secondary nucleation site’. They drive monomeric αSyn to aggregation. Small molecules targeting these motifs are promising for disease-modifying therapy. Using computational techniques, we screened thirty phytochemicals for αSyn binding. The top three compounds were experimentally validated for their binding affinity. Amongst them, celastrol showed high binding affinity. NMR analysis confirmed stable αSyn-celastrol interactions involving several residues in the N-terminus and NAC regions but not in the C-terminal tail. Importantly, celastrol interacted extensively with the key motifs that drive αSyn aggregation. Thioflavin-T assay indicated that celastrol reduced αSyn aggregation. Thus, celastrol holds promise as a potent drug candidate for PD. Communicated by Ramaswamy H. Sarma

α-突触核蛋白（α-Synuclein，αSyn）聚集与帕金森病（Parkinson’s Disease，PD）密切相关。αSyn_36-42区域作为成核“主控因子”，αSyn_1-12则为“次级成核位点”，二者可驱动单体αSyn发生聚集。靶向这些基序的小分子化合物有望用于帕金森病的疾病修饰治疗。本研究通过计算技术筛选了30种可结合αSyn的植物化学物，选取排名前三的化合物开展结合亲和力实验验证。其中，雷公藤红素（celastrol）展现出较高的结合亲和力。核磁共振（Nuclear Magnetic Resonance，NMR）分析证实，αSyn与雷公藤红素可形成稳定的相互作用，该作用涉及N端及NAC区域的多个残基，但不涉及C端尾区。尤为重要的是，雷公藤红素可与驱动αSyn聚集的关键基序广泛结合。硫黄素T（Thioflavin-T，ThT）检测结果显示，雷公藤红素可抑制αSyn聚集。综上，雷公藤红素有望成为治疗帕金森病的强效候选药物。本文由Ramaswamy H. Sarma通讯。