We are interested in using chemistry to understand biological processes. Central to our theme is organic chemistry as a tool that intersects with molecular life sciences such as molecular and cell biology. Our primary focus is the development of chemical toolboxes to address problems in biology. Currently, our work is aimed at the following:
Development of novel diboron reagents for the mild and selective boration of activated carbon-carbon bonds
We recently reported the synthesis and characterization of a novel sp2-sp3 diboron reagent that allows the b-boration of a,b-unsaturated conjugated compounds. The reaction proceeds under mild conditions with various substrates, i.e., a,b-unsaturated esters, ketones, nitriles, ynones, amides, and aldehydes, in the absence of additives such as phosphine and sodium tert-butoxide.
Development of medium-sized branched peptides to target RNA structures associated with HIV as the next generation anti-HIV therapeutics
It has been 27 years since HIV-1 (human immunodeficiency virus) was identified as the causative agent for AIDS (acquired immunodeficiency syndrome). More than 60 million people worldwide have been infected with HIV-1, mostly in the developing world, and nearly half of these individuals have died. An estimated 33 million people were living with HIV in 2007. While the annual number of new HIV infection declined from 3 million in 2001 to 2.7 million in 2007, 2 million people died due to AIDS in 2007. To date, the percentage of people living with HIV has steadily increased as new infections occur each year and as HIV treatments extend life. Most of the current drugs in use for the treatment of AIDS work by combination targeting of the enzymatic activities of the HIV reverse transcriptase and/or protease (HAART, highly active anti-retroviral therapy) and/or gp41. These treatments remain expensive and are often not well-tolerated by patients. Presently, viral entry and integrase inhibitors offer promise as novel targets. Because of the emergence of drug-resistant virus that commonly occurs as the result of classical HIV treatment, there remains a great need to continue the search for alternative therapies that target other essential viral activities. Thus, the development of new drugs with novel mode of action is of utmost urgency. Our group is developing branched peptides that recognize conserved, structured RNA elements of the virus as the next generation anti-HIV therapeutics.
Defining the roles of sphingosine kinases in hyperproliferative diseases by developing cell permeable small molecule libraries as probes
Sphingosine kinases (SphKs) are the master regulator of the balance between the pro-survival sphingolipid, sphingosine-1-phosphate (S1P) and the pro-apoptotic sphingolipids, sphingosine (Sph) and ceramide. SphKs, in particular SphK1, are overexpressed in a variety of tumor types including breast, prostate, ovary, liver, glioblastoma, etc. Because of its key role in sphingolipid metabolism, SphK is an attractive target for anticancer drugs and has been suggested more recently to be a target for anti-inflammatory therapeutics. However, the field has suffered from the paucity of SphK inhibitors with the selectivity and drug-like properties needed for testing such ideas. Thus we are developing the compounds necessary to validate this enzyme as a therapeutic target.