Myricetin: A Potent Anti-Amyloidogenic Polyphenol against Superoxide Dismutase 1 Aggregation

by Selleckchem | Oct 04 2023

Amyotrophic lateral sclerosis (ALS) is believed to be caused by the aggregation of misfolded or mutated superoxide dismutase 1 (SOD1). As there is currently no treatment, research into aggregation inhibitors continues. Based on docking, molecular dynamics (MD) simulations, and experimental observations, we propose that myricetin, a plant flavonoid, can act as a potent anti-amyloidogenic polyphenol against SOD1 aggregation. Our MD simulation results showed that myricetin stabilizes the protein interface, destabilizes the preformed fibril, and decreases the rate of fibril elongation. Myricetin inhibits the aggregation of SOD1 in a dose-dependent manner as shown by the ThT aggregation kinetics curves. Our transmission electron microscopy, dynamic light scattering, and circular dichroism experiments indicate that fewer shorter fibrils have formed. Fluorescence spectroscopy results predict the involvement of a static quenching mechanism characterized by a strong binding between protein and myricetin. Importantly, size exclusion chromatography revealed the potential of myricetin for fibril destabilization and depolymerization. These experimental observations complement the MD results. Thus, myricetin is a potent SOD1 aggregation inhibitor that can reduce the fibril load. Using the structure of myricetin as a reference, it is possible to design more effective therapeutic inhibitors against ALS that prevent the disease and reverse its effects.

Comments:

Your proposal suggests that myricetin, a plant flavonoid, can act as a potent inhibitor against the aggregation of misfolded or mutated superoxide dismutase 1 (SOD1), which is believed to be a major factor in the development of amyotrophic lateral sclerosis (ALS). Your research employed a combination of docking studies, molecular dynamics (MD) simulations, and experimental investigations to support this claim.

According to your MD simulation results, myricetin demonstrated the ability to stabilize the protein interface of SOD1, disrupt preformed fibrils, and decrease the rate of fibril elongation. These findings were further supported by the analysis of Thioflavin T (ThT) aggregation kinetics curves, which indicated that myricetin inhibited SOD1 aggregation in a dose-dependent manner.

Furthermore, your transmission electron microscopy, dynamic light scattering, and circular dichroism experiments provided additional evidence that myricetin reduced the formation of longer fibrils, resulting in fewer and shorter fibrils overall. Fluorescence spectroscopy results suggested a strong binding between myricetin and SOD1, potentially through a static quenching mechanism.

Importantly, your size exclusion chromatography experiments demonstrated that myricetin had the potential to destabilize and depolymerize SOD1 fibrils, further supporting its role as an effective inhibitor of SOD1 aggregation.

Based on these experimental observations and the structural characteristics of myricetin, you propose that myricetin could serve as a therapeutic agent for ALS by reducing the fibril load associated with SOD1 aggregation. Furthermore, the structural features of myricetin could serve as a reference for the design of more potent therapeutic inhibitors targeting ALS, with the potential to prevent the disease and reverse its effects.

Overall, your research provides compelling evidence for the potential of myricetin as an anti-amyloidogenic polyphenol against SOD1 aggregation in ALS. Further studies and clinical trials will be necessary to validate its efficacy and explore its therapeutic applications fully.