When the varieties of mitochondrial conditions are pooled together, dysfunctional mitochondria become a major source of disease, affecting primarily the very young, but also increasingly older adults as part of the aging process.
Disease-causing defects are centered within the energy transduction pathways of mitochondria, which ultimately produce energy in the form of ATP.
Although the macro elements of the different enzymes are well known, a detailed map and systems biology understanding of the chemical events and their regulation is currently ill-defined. Drug discovery efforts have been hampered due to mitochondria carrying out a distinct type of oxidation-reduction, or redox chemistry.
Traditional medicinal chemistry libraries are devoid of redox compounds and standard systems biology assays omit oxidative elements from their analysis. Our efforts hope to combine both research and translational aspects of discovery in order to break through the current bottlenecks in fundamental mitochondrial biochemistry, drug design and therapeutic compounds.
Our research can be broadly divided into three primary areas:
- Understanding nature’s biochemical energy lexicon—the energy code
- Identification of chemical scaffolds to enable therapeutic design
- Design of systems biology models predictive of human function
Biological chemistry and drug design
An important new research initiative involves elucidating the chemical mechanism of mitochondrial energy production and an analysis of the effects of specific mitochondrial defects. At present, we are focused on mitochondrial complexes I and II, and the way in which electrons are transported through these complexes, and then to complex III. The strategy involves the use of substrate analogues and inhibitors, in conjunction with biochemical and cellular assays, to dissect function at the molecular level.
Biochemical drug classes include:
Dr. Hecht has more than three decades of experience in academic and industrial research positions as a biological chemist and drug designer, and also serves on the boards of several biotech companies. In 2005, he co-founded Edison Pharmaceuticals with Dr. Guy Miller. The company focuses on drugs for inherited mitochondrial diseases.
Translational aspects of our research program include:
- Development of biomarkers to enable optimization and therapeutic evaluation
- Chemical optimization using systems biology screens
- Advance small molecules into therapeutic evaluation
Due to widely ranging symptoms and early lack of understanding of the root cause of these symptoms, mitochondrial diseases have historically been classified into discreet groupings of diseases, such as Friedreich’s Ataxia, that are relatively rare. This meant little effort has been put into drug discovery and treatment. Yet, together, the more than 40 mitochondrial diseases comprise a significant human and health care burden.