Naphthoquinone–Dopamine Hybrids Inhibit α‐Synuclein Aggregation, Disrupt Preformed Fibrils, and Attenuate Aggregate‐Induced Toxicity

Abstract

Accumulationa nd aggregation of the intrinsically disordered protein a-synuclein (a-Syn) into amyloid fibrils are hallmarks of as eries of heterogeneous neurodegenerative disorders, known as synucleinopathies and most notably Parkinson's disease (PD). The crucial role of a-Syn aggregation in PD makes it an attractive targetf or the development of disease-modifying therapeutics that would inhibit a-Syn aggregation or disrupti ts preformed fibrillara ssemblies. To this end, we have designed and synthesized two naphthoquinone-dopamine-basedh ybrid small molecules, NQDA and Cl-NQDA, and demonstrated their abilityt oi nhibit in vitro amyloid formation by a-Syn using ThT assay,C D, TEM, and Congo red birefringence.M oreover, these hybrid molecules efficiently disassembled preformed fibrils of a-Syn into nontoxic species, as evident from LUV leakage assay. NQDA and Cl-NQDA were found to have low cytotoxicity andt hey attenuated the toxicityi nduced by a-Syn towards SH-SY5Y neuroblastoma cells. NQDA was found to efficiently cross an in vitro human blood-brain barrier model. These naphthoquinone-dopamine based derivativesc an be an attractive scaffold for therapeuticd esign towards PD.

Inhibition of tau amyloid formation and disruption of its preformed fibrils by Naphthoquinone–Dopamine hybrid

“…Naphthoquinone-dopamine was synthesized as described previously [38]. Synthesized NQDA was characterized by HPLC, mass spectrometry, and 1 HNMR spectroscopy (Figs S1-S3).…”

“…11). Notably, the NQDA hybrid molecule was found to efficiently cross a model of blood-brain barrier, which is valuable from therapeutic perspective and to be an efficient inhibitor of aggregation of α-synuclein, associated with PD [38]. NQDA could thus be a useful scaffold for designing novel therapeutics toward AD or other tauopathies.…”

“…We hypothesized that in NQDA, the aromatic moiety of DA would intercalate within the β‐sheets of the amyloidogenic protein and the quinone part together with the two hydroxyl groups of DA will interfere with the self‐aggregation process to inhibit amyloid formation. We have demonstrated that NQDA is an effective inhibitor of α‐synuclein aggregation [38]. Here, we tested the ability of NQDA to modulate aggregation of the tau protein.…”

Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease

“…The de novo compound exerts a beneficial role in the reduction of a-syn in both neuronal cells and three different a-syn transgenic rodent models (121). Table 2 summarizes other molecules or compounds aimed at the disaggregation of a-syn, including FLZ (122), CMT-3 (123), aSyn-323.1 (124), hydroxytyrosol (125), NQDA (126), Fasudil (127,128), and D-520 (129).…”

Glucosylceramide Associated with Gaucher Disease Forms Amyloid-like Twisted Ribbon Fibrils That Induce α-Synuclein Aggregation

“…ThT fluorescence assay was carried out in a similar manner as described previously to monitor the protein aggregation. 69 In brief, to monitor the aggregation kinetics of GlcCer, the stock solutions were diluted in 100 μL wells in a 96-well black plate so that the final mixture contained 10–200 μM of GlcCer and 20 μM ThT in 100 mM PBS (or in AB). For the aggregation kinetic of αSyn, the final concentration was used as 10 μM from the stock of 50 μM in 100 mM PBS (or in AB).…”