Activity modulators of the calcium ATPases
The sarco/endoplasmic reticulum calcium ATPase (SERCA) belongs to the family of P-type ATPases, a large class of transmembrane proteins that use the energy gained from hydrolysis of ATP to transport cations across membranes. By pumping calcium ions into intracellular storage compartments, SERCA plays an important role in a variety of vital physiological processes, such as skeletal muscle contraction and relaxation or signal transduction. The ion transport activity of SERCA is inhibited by several classes of structurally unrelated compounds that include derivatives of the sesquiterpene lactone thapsigargin, the fungal metabolite cyclopiazonic acid, the polyphenol curcumin, and alkylated hydroquinones. Although primarily used as powerful research tools for the study of calcium homeostasis, some SERCA inhibitors also have shown promise as novel prodrugs for the treatment of prostate cancer. Moreover, the potential hazard to human health posed by certain SERCA inhibitors found in the environment has become a growing concern.
In a related project, we are studying the ability of small compound to inhibit a P-type calcium ATPase found in Plasmodium falciparum, the parasite causing malaria. Here, the ultimate goal is to develop new inhibitors that bear potential as antimalarial drugs in the future.
In a related project, we are studying the ability of small compound to inhibit a P-type calcium ATPase found in Plasmodium falciparum, the parasite causing malaria. Here, the ultimate goal is to develop new inhibitors that bear potential as antimalarial drugs in the future.
The Origin of Life
The goal of this line of research is to mimic rather primitive living systems as they may have existed on early earth, using liposomes as models for primordial cells (left panel). We are currently testing the ability of structurally simple inorganic compounds to initiate electron transfer reactions (middle panel), which in turn facilitate the transport of protons across the liposomal lipid bilayers that is monitored with a fluorescent pH-sensitive dye (right panel). This process is vital for the generation of energy in all modern organisms on earth today and must have evolved from much simpler systems. In addition to testing inorganic compounds, we plan on identifying primitive lipid-like molecules capable of forming bilayers stable enough to maintain proton gradients in primeval cells. This project entails the preparation of liposomes with an encapsulated fluorescent dye that serves as a pH probe. The research is conducted in collaboration with David Deamer (UC Santa Cruz emeritus), who is a renowned expert in this field.
Inhibitors of the sodium/potassium ATPase (Na/K-ATPase)
Even after over 200 years of use, cardiac glycosides (digitalis) are still frequently prescribed for the treatment of congestive heart failure symptoms. They exert their therapeutic effect by inhibiting the ion-transporting activity of Na/K-ATPase in the membrane of heart muscle cells. As a result of the inhibition, the transmembrane sodium concentration gradient decreases which slows the exchange of intracellular calcium ions against extracellular sodium ions. The resultant consequence is a rise in intracellular calcium concentration, which is the main cause of the so-called positive inotropic effect. The latter constitutes an increase in the contractile force of the heart muscle and cardiac output, which alleviates symptoms of congestive heart failure. Despite their effectiveness, cardiac glycosides such as digoxin or digitoxin have the disadvantage of a relatively low therapeutic index, which increases the likelihood for toxicity that can trigger life-threatening heart arrhythmias. For this reason, the availability of Na/K-ATPase inhibitors with larger therapeutic indices would be of great therapeutic value for the treatment of congestive heart failure symptoms.
Inhibitors of Xanthine Oxidase (XO)
The enzyme XO plays an important role in purine catabolism by catalyzing the conversion of xanthine and hypoxanthine to uric acid. For decades, XO inhibition by allopurinol has been used as an effective treatment of gout caused by hyperuricemia. Problems of allopurinol-based treatments relate to the drug's relatively low potency, requiring relatively high doses that raise the likelihood of adverse effects. As the approval of the new XO inhibitor febuxostat in 2009 illustrates, the development of alternative XO inhibitors based on novel structural scaffolds continues to be an active field of current research.
More recently, XO inhibition has been suggested to be useful for the suppression of oxidative stress in tissue caused by elevated levels of reactive oxygen species. The latter are known to cause conditions such as reperfusion injuries that can occur after surgery or ischemic events (heart attacks and strokes). We are interested in designing compounds capable of lowering reactive oxygen species levels by inhibiting their generation by XO and by directly scavenging radicals.
More recently, XO inhibition has been suggested to be useful for the suppression of oxidative stress in tissue caused by elevated levels of reactive oxygen species. The latter are known to cause conditions such as reperfusion injuries that can occur after surgery or ischemic events (heart attacks and strokes). We are interested in designing compounds capable of lowering reactive oxygen species levels by inhibiting their generation by XO and by directly scavenging radicals.
Ligands of the Arylhydrocarbon Receptor (AhR)
Ligands capable of binding to the AhR and hijacking its signaling pathway are of potential use for the design of novel agents against breast cancer. To guide the synthesis of new compounds and characterize their binding to the AhR, we employ homology modeling, ligand docking, and molecular dynamics simulations. For example, we have simulated the binding of several phenylacrylonitriles that have activity against cancer cell lines. Our computational analysis supports the synthetic work done by the group of Adam McCluskey at the University of Newcastle, Australia.