Autoxidation Enhances Anti-Amyloid Potential of Flavone Derivatives.

Andrius Sakalauskas,Ruta Snieckute,Vytautas Smirnovas,Mantas Ziaunys

doi:10.3390/antiox10091428

Andrius Sakalauskas, Ruta Snieckute + Show 2 more

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https://doi.org/10.3390/antiox10091428

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Journal: Antioxidants	Publication Date: Sep 7, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Vilnius University

Abstract

The increasing prevalence of amyloid-related disorders, such as Alzheimer’s or Parkinson’s disease, raises the need for effective anti-amyloid drugs. It has been shown on numerous occasions that flavones, a group of naturally occurring anti-oxidants, can impact the aggregation process of several amyloidogenic proteins and peptides, including amyloid-beta. Due to flavone autoxidation at neutral pH, it is uncertain if the effective inhibitor is the initial molecule or a product of this reaction, as many anti-amyloid assays attempt to mimic physiological conditions. In this work, we examine the aggregation-inhibiting properties of flavones before and after they are oxidized. The oxidation of flavones was monitored by measuring the UV-vis absorbance spectrum change over time. The protein aggregation kinetics were followed by measuring the amyloidophilic dye thioflavin-T (ThT) fluorescence intensity change. Atomic force microscopy was employed to image the aggregates formed with the most prominent inhibitors. We demonstrate that flavones, which undergo autoxidation, have a far greater potency at inhibiting the aggregation of both the disease-related amyloid-beta, as well as a model amyloidogenic protein—insulin. Oxidized 6,2′,3′-trihydroxyflavone was the most potent inhibitor affecting both insulin (7-fold inhibition) and amyloid-beta (2-fold inhibition). We also show that this tendency to autoxidize is related to the positions of the flavone hydroxyl groups.

Highlights

Protein aggregation into highly structured aggregates is associated with various amyloidoses, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [1]
We show that the positions of flavone hydroxy groups have a remarkably high impact on autoxidation which enables the inhibitory effect on both proteins under the tested conditions
The rest of the flavones had minor spectra changes during incubation that are reflected in slight transitions of the maxima positions (No 30, 45, 54, 56, 60, 62) or a decrease in the magnitude of the maxima in the

Summary

Introduction

Protein aggregation into highly structured aggregates is associated with various amyloidoses, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [1]. AD alone is recognized to be the most common cause of dementia (60–80%) [2] that affects more than 50 million people worldwide and, according to the World Alzheimer’s Report, is set to increase up to 152 million by 2050 The cause of this forecast is that the onset of AD mostly occurs after 60 years of age, and the increasing life expectancy leads to more people suffering from dementia. The increasing focus on anti-amyloid-β compounds has led to many different in vitro studies showing positive effects against protein aggregation [4]. Despite this fact, many suggested disease-modifying compounds, ranging from small organic molecules to large monoclonal antibodies, have not led to an effective cure, leaving 99.5% of clinical trials unsuccessful [5,6]. It is of utmost importance to take into consideration the gap between the initial drug screening and human physiology [4,9]

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