KH176 Safeguards Mitochondrial Diseased Cells from Redox Stress-Induced Cell Death by Interacting with the Thioredoxin System/Peroxiredoxin Enzyme Machinery

Julien Beyrath,Peter Van Zandvoort,Lisanne Houben,Svetlana Pecheritsyna,Petra Van Den Broek,Akkiz Bekel,Jan A M Smeitink,Herma Renkema,Pierre Eftekhari,Mina Pellegrini

doi:10.1038/s41598-018-24900-3

Abstract

A deficient activity of one or more of the mitochondrial oxidative phosphorylation (OXPHOS) enzyme complexes leads to devastating diseases, with high unmet medical needs. Mitochondria, and more specifically the OXPHOS system, are the main cellular production sites of Reactive Oxygen Species (ROS). Increased ROS production, ultimately leading to irreversible oxidative damage of macromolecules or to more selective and reversible redox modulation of cell signalling, is a causative hallmark of mitochondrial diseases. Here we report on the development of a new clinical-stage drug KH176 acting as a ROS-Redox modulator. Patient-derived primary skin fibroblasts were used to assess the potency of a new library of chromanyl-based compounds to reduce ROS levels and protect cells against redox-stress. The lead compound KH176 was studied in cell-based and enzymatic assays and in silico. Additionally, the metabolism, pharmacokinetics and toxicokinetics of KH176 were assessed in vivo in different animal species. We demonstrate that KH176 can effectively reduce increased cellular ROS levels and protect OXPHOS deficient primary cells against redox perturbation by targeting the Thioredoxin/Peroxiredoxin system. Due to its dual activity as antioxidant and redox modulator, KH176 offers a novel approach to the treatment of mitochondrial (-related) diseases. KH176 efficacy and safety are currently being evaluated in a Phase 2 clinical trial.

Highlights

Compartments, such as catalase, superoxide dismutases and peroxiredoxins, as well as non-enzymatic systems, such as glutathione (GSH), ascorbic acid and α-tocopherol[7,8]
An increase in Reactive Oxygen Species (ROS) level can lead to a redox imbalance, we noted that this correlation was not necessarily seen in all patient cell lines
During pharmacokinetics and metabolism studies of KH176 in vivo in different animal species the formation of a major metabolite - KH176m - was reported, and evaluated in vitro along with KH176

Summary

Introduction

Compartments, such as catalase, superoxide dismutases and peroxiredoxins, as well as non-enzymatic systems, such as glutathione (GSH), ascorbic acid and α-tocopherol[7,8]. Genetic defects of subunits of the OXPHOS complexes can result in increased ROS production leading to aberrations in the redox-controlled cell signalling, such as the thiol-based signalling, and to irreversible damaging oxidation of macromolecules such as lipid peroxidation or protein carbonylation[16,17,18]. This cellular condition is often referred to as “oxidative stress” underlying the shift of the cellular redox balance towards a more oxidized environment[7,19]. We show that the activity of KH176 is depending on its redox potential and on proper functioning thioredoxin system/peroxiredoxin enzyme machinery

Methods

Results

Conclusion