For many pharmaceutical companies, drug safety assessments are still made fairly late in the drug discovery process. However, it is clear that safety testing should be one of the first steps in the selection of lead compounds, especially when a great variety of compounds exist to support the creation of structure-activity relationships (SAR). The adoption of newer in vivo, in vitro and in silico tools and the use of new and promising technologies must be the priority for pharmaceutical companies in order to increase drug safety.
It is now apparent that mitochondrial toxicology has become an area of interest to the industry, since a primary assessment of mitochondrial toxicity of a range of compounds can be performed in a fast and relatively inexpensive way, avoiding some later human toxicity problems that may arise during subsequent testing stages or even during clinical use (Pereira et al., 2009). Indeed mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities. Members of diverse drug classes undermine mitochondrial function, and among the most potent are drugs that have been withdrawn from the market, or have received Black Box warnings from the FDA. To avoid mitochondrial liabilities, routine screens need to be positioned within the drug-development process (Dickens & Will, 2007). We should expect to see in the future an increasing number of pharmaceutical companies establishing protocols to assess mitochondrial toxicity of novel molecules under study in a fast and inexpensive way.
Since the dominant function of mitochondria is the production of cellular energy through OXPHOS, the assessment of OXPHOS health and impairment has become the focal point of mitochondrial analysis. However, most traditional techniques for such analyses suffer from low throughput, time-consuming mitochondrial isolation steps and the non-physiological conditions associated with the detachment of mitochondria from the cellular environment. Metabiolab quantitatively detect multiple intact OXPHOS complexes from cell lysates or tissue extracts. These panels demonstrate the potential broad applications in the study of mitochondrial dysfunction-associated diseases in order to better understand disease mechanisms and to discover potential treatments. They can potentially be used in the drug development process to predict mitochondrial impairment-linked drug-induced toxicity, thus correspondingly reducing late-stage drug attrition and improving drug safety.
Several models can efficiently be addressed by our platform. These models will fit with all human medical applications where metabolism dysfunction is involved.
The involvement of oxidative stress in Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), suggest that free radicals play important roles in the onset and progress of neurodegenerative process. The investigation of mitochondrial diseases as a model of neurodegenerative diseases, is useful for defining the role of these organelles in normal and pathological conditions. (Federico et al., 2012; Sultana et al., 2013)
The oxidative stress is an important trigger in the complex chain of events leading to and promoting atherosclerosis. The expression of chemotactic factors such as monocyte chemotactic protein-1 (MCP-1/CCL2) is enhanced by oxidative stress and oxidized LDLs. Oxidized LDLs, stimulates the release of interleukin-1 from macrophages. The activity of MMPs is also regulated by oxidative stress and appears to be closely linked to smooth muscle cell activation and migration. MMPs have also been implicated in the physiopathology of plaque rupture. Furthermore, ROS can lead to platelet activation and thrombus formation. Therefore, oxidative stress appears to be important in both the early and later stages of the atherosclerotic process. (Tardif, 2003)
A chronic elevation of glucose leads to the generation of reactive oxygen species (ROS), resulting in increased oxidative stress in β-cells. As a result, β-cells become worsened with respect to both insulin secretion and action due to their ability to directly damage and oxidize DNA, protein, and lipids. In addition to macromolecular damage, ROS can activate a number of cellular stress-sensitive pathways that have been linked to insulin resistance and decreased insulin secretion. In order to neutralize ROS, cells are equipped with antioxidant defense mechanisms capable of combating oxidative stress. Intriguingly, compared to other tissues, β-cells have a lower abundance of antioxidant defense enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). Thus, due to the low antioxidant defense status of islets, excessive ROS lead to oxidative stress during β-cell dysfunction.
Metabolism modification is one of the modes of action of various therapeutically applied substances. One of the main targets in the cell is mitochondria and drugs targeting mitochondria are of the utmost importance. Indeed, some of these substances are specifically designed to affect mitochondrial functions. In other cases, drugs with primary targets in other cellular locations may modify mitochondrial functions as side effects. In any case, identification of mitochondria as primary or secondary targets of a drug may help to better understand the drug’s mechanism of action and open new perspectives for its application. (Alfarouk et al., 2014; Bhatt et al., 2010; Cuezva et al., 2002; Frantz & Wipf, 2010; Szewczyk & Wojtczak, 2002; Choi et al., 2011).
Preclinical and clinical data have demonstrated the considerable potential of mitochondrial targeting approaches, and potential therapeutic applications span a broad range of pathological conditions. Clearly, a better understanding of the mitochondrial biology is still needed to enable the design of the most beneficial therapeutic approach with respect to the modulation of the redox balance of the targeted cells. Nonetheless, the increasing prevalence of age-related disorders calls for innovative solutions, and mitochondrial drugs clearly have the potential to emerge as a key platform technology for the next generation of medicines.
Clinical phase study
As an important part of patients monitoring during clinical phases, markers of cellular metabolism will become an indisputable mean to precisely evaluate drug normal or side effects.