Synthesis and Identification of Novel Aromatic Compound as Inhibitor of Lysozyme Amyloid Aggregation

Alzheimer's disease is of major concern all over the world due to a number of factors including (i) an aging population (ii) increasing life span and (iii) lack of effective pharmacotherapy options. Aromatic small molecules have been found to play a neuroprotective role by inhibiting and/or modifying the self-assembly of peptide or proteins into oligomers and fibrils, which are linked to the pathogenesis of the diseases. In this study, the inhibitory effects of 1,3, 5 triphenyl benzene as an aromatic molecule on aggregation and neurotoxicity of hen egg white lysozyme (HEWL) was investigated.

Acidic pH and high temperatures were used to drive the protein towards amyloid formation. Lysozyme was dissolved at 2 mg/mL in 50mM glycine buffer (pH 2.5), and then incubated at 57 °C for the specified durations. The inhibitory effect of the compounds against hen egg white lysozyme (HEWL) fibrillation using AFM (atomic force microscope), ThT (thioflavin T), Congo red and MTT assay was investigated.

We found that the compounds is able to inhibit HEWL aggregation in a dose-dependent manner with IC50 0.1 µM. Kinetic study of the compound caused lag phase prolonged and stationary phase decreased and also cytotoxic activity of HEWL aggregates in presence of the compounds was diminished.

These observations suggest that 1,3,5 triphenyl benzene is capable to insert directly into amyloidogenic core of early aggregates and inhibiting amyloid fibril formation.