Naphthoquinone-Dopamine hybrids inhibit  α-synuclein aggregation, disrupt preformed fibrils and attenuate aggregate-induced toxicity.

Naphthoquinone-Dopamine hybrids inhibit α-synuclein aggregation, disrupt preformed fibrils and attenuate aggregate-induced toxicity. Chemistry. 2020 Sep 01;: Authors: Paul A, Huber A, Rand D, Gosselet F, Cooper I, Gazit E, Segal D Abstract Accumulation and aggregation of the intrinsically disordered protein α-synuclein (α-Syn) into amyloid fibrils are hallmarks of a series of heterogeneous neurodegenerative disorders, known as synucleinopathies and most notably Parkinson's disease (PD). The crucial role of α-Syn aggregation in PD makes it an attractive target for the development of disease-modifying therapeutics that would inhibit α-Syn aggregation or disrupt its preformed fibrillar assemblies. To that end, we have designed and synthesized two naphthoquinone-dopamine-based hybrid small molecules, NQDA and Cl-NQDA, and demonstrated their ability to inhibit in vitro amyloid formation by α-Syn using ThT assay, CD, TEM, and Congo red birefringence. Moreover, these hybrid molecules efficiently disassembled preformed fibrils of α-Syn into non-toxic species, as evident from LUV leakage assay. NQDA and Cl-NQDA were found to have low cytotoxicity and they attenuated the toxicity induced by α-Syn towards SH-SY5Y neuroblastoma cells. NQDA was found to efficiently cross an in vitro human blood-brain barrier model. These naphthoquinone-dopamine based derivatives can be an attractive scaffold for therapeutic design towards PD. PMI...
Source: Chemistry - Category: Chemistry Authors: Tags: Chemistry Source Type: research