Cancer cells have a very different metabolism from that of normal cells from which they are derived. Glycolysis, although enhanced in cancer cells, is no longer a source of biosynthetic precursors. Instead, glutaminolysis fuels the TCA cycle with glutamine-derived α-ketoglutarate. The enhanced production of α-ketoglutarate is critical to cancer cells as it provides carbons and nitrogens for the TCA cycle to produce glutathione, fatty acids, nucleotides, hexosamines, nucleotides, and many nonessential
amino acids. Glutaminase and isocitrate dehydrogenase are two critical enzymes in the production of α-ketoglutarate in cancer cells. A lot of times, when one metabolic pathway in cancer cells is blocked, they shift to enhance alternative metabolic pathways to maintain the production of essential molecules. Development of inhibitors for both critical enzymes in the α-ketoglutarate production allows us to study the effects on cancer cells when one of the enzymes is inhibited, as well as when both of the enzymes are inhibited.
which catalyzes the ubiquinone-mediated oxidation of dihydroorotate to orotate, in the pyrimidine biosynthesis pathway. The pyrimidine biosynthesis pathway is critical for the survival of P. falciparum because it cannot salvage pyrimidines and therefore is completely dependent on de novo pyrimidine synthesis. Inhibition of either cytochrome bc1 complex or dihydroorotate dehydrogenase has been shown to result in death of the parasite. We are currently focusing on the development of inhibitors of cytochrome bc1 complex.
Salvinorin A, one of the most potent naturally occurring opioid agonists with high selectivity and affinity for KOR
Cytochrome bc1 complex is a dimeric multisubunit electron transport protein in the inner-mitochondrial membrane and is a proven drug target in the prevention and treatment of malaria. Cytochrome bc1 complex is essential for Plasmodium falciparum as it maintains a pool of ubiquinone for the enzyme dihydroorotate dehydrogenase,
Metabolism in normal cells vs. one in cancer cells. The figure was originally published by Erickson and Cerione.
κ-Opioid Receptor (KOR) Research
The κ-opioid receptor (KOR) is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. KOR agonists have provided therapeutic potential in the treatment of pain and convulsion, and as antidotes for opioid overdose, while KOR antagonists have proven useful in drug abuse relapse, depression, and anxiety.
Atovaquone, the only current FDA-approved inhibitor of Plasmodium falciparum cytochrome bc1 complex
However, the development of current KOR ligands as therapeutic agents has been hindered by their unfavorable side effects. Current KOR agonists produce dysphoria, sedation, and depression due to their low functional selectivity, while current KOR antagonists possess unusually long pharmacokinetic profiles due to their long-acting effect. We are currently aiming to solve these problems for KOR agonists and antagonists.