Novel Mannitol-Based Small Molecules for Inhibiting Aggregation of α-Synuclein Amyloids in Parkinson's Disease

The aggregation of the amyloidogenic protein a-synuclein (alpha-Syn) into toxic oligomers and mature fibrils is the major pathological hallmark of Parkinson's disease (PD). Small molecules that inhibit alpha-Syn aggregation thus may be useful therapeutics for PD. Mannitol and naphthoquinone-tryptophan (NQTrp) have been shown in the past to inhibit alpha-Syn aggregation by different mechanisms. Herein, we tested whether the conjugation of Mannitol and NQTrp may result in enhance efficacy toward alpha-Syn. The molecules were conjugated either by a click linker or via a PEG linker. The effect of the conjugate molecules on alpha-Syn aggregation in vitro was monitored using Thioflavin T fluorescence assay, circular dichroism, transmission electron microscopy, and Congo red birefringence assay. One of the conjugate molecules was found to be more effective than the two parent molecules and as effective as a mixture of the two. The conjugate molecules attenuated the disruptive effect of alpha-Syn on artificial membrane of Large Unilamellar Vesicles as monitored by dye leakage assay. The conjugates were found to be have low cytotoxicity and reduced toxicity of alpha-Syn toward SH-SY5Y neuroblastoma cells. These novel designed entities can be attractive scaffold for the development of therapeutic agents for PD.