Ph: (217) 333 1630, FAX: (217) 244 6615, E-Mail: biophysics@life.illinois.edu
Director: Robert M Clegg Administrative Coordinator: Cindy Dodds
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Faculty Profiles
We are interested in developing new drugs effective in the treatment of infectious diseases (sleeping sickness, malaria, tuberculosis and HIV/AIDS), bone resorption diseases, cholesterol-lowering agents and cancer. We design and synthesize novel drug molecules using a combination of x-ray crystallography, NMR and computational chemistry to guide the design aspects, followed by synthesis and testing, in an interactive manner. We are currently working with some 20 groups worldwide, comprised of immunologists, parasitologists and other infectious disease specialists. The drugs we are developing act primarily as inhibitors of the mevalonate/isoprene pathway – where current drugs represent a $20 billion market worldwide. In our group, we have found that inhibitors of this pathway have potent anti-parasitic activity. These inhibitors are primarily bisphosphonates and act as aza-carbocation reactive intermediates and are effective at low nM concentrations. These compounds kill many protozoan parasites, including those responsible for malaria, sleeping sickness, Chagas’ disease, toxoplasmosis (AIDS encephalitis), cryptosporidiosis (AIDS diarrhea), leishmaniasis and amebic dysentery. These diseases afflict some 500 million individuals worldwide, resulting in ~3 million deaths. In our group, we have already found animal cures of two major forms of leishmaniasis (which affect ~1-2 million individuals in the Middle and Far East and in Latin America) and we are using the results of enzyme inhibition and animal testing to try to develop effective, low-cost treatments for these and the other major, parasitic diseases. It has also recently been found that bisphosphonates and related systems have major stimulatory effects on the human immune system where they stimulate gd T cells. These T cells represent the first line of defense against infectious agents and most likely, in tumor immune surveillance. Many dangerous pathogens produce analogs of the mevalonate/isoprene pathway metabolites and some tumor cells overexpress these metabolites. The gd T cells recognize these cells as "foreign" and mount an attack on both the pathogens and tumor cells. For example, the organisms responsible for causing malaria, tuberculosis, plague, anthrax and tularemia all produce such immunostimulatory molecules, as do tumor cells. These and related compounds, collectively known as "phosphoantigens" (to distinguish then from more conventional, peptide antigens, recognized by ab T cells) are now being developed by our group as anti-infective and anti-cancer drugs. We are also interested in the development of anti-HIV/AIDS drugs. HIV drug resistance is a very serious problem in long-term therapy of HIV-infected individuals, and there are increasing numbers of patients who no longer respond to any of the approved therapeutics. There is therefore a critical need to identify new therapeutics, as well as to identify therapeutic strategies that may prolong current drug utility. It has recently been found that HIV resistance to zidovudine (AZT) involves reverse transcriptase-mediated excision of incorporated AZTMP, and that this excision proceeds via pyrophosphorolysis. We are searching for potential inhibitors of this pyrophosphorolytic excisition, since such inhibitors may prolong therapeutic efficacy of drugs such as AZT. Overall, we thus have projects/interests in the following areas, for new students:
For more, go to our Web page (http://feh.scs.illinois.edu). |
