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We are interested in how the simple nucleotide dUTP plays a role in the action of several antimetabolite drugs and how dUTP pool levels are used as an innate immune defense against viruses. We investigate the mechanisms for both of these uracil-centric problems using advanced biophysical and cell biology approaches. Our goal is to uncover new targets for antiviral and anticancer therapeutic development.
DNA repair enzymes must locate rare damaged bases in a large sea of undamaged bases. We have developed new methods for unraveling the fundamental mechanisms that are used to search for DNA damage. Current questions being investigated are the role of DNA and enzyme electrostatics in the process of DNA translocation, how enzymes recognize damage in the context of nucleosomes, and the development of model systems for investigating the biophysics of DNA damage recognition in crowded environments such as the human nucleus.
The immune system uses both adaptive (antibody) and innate mechanisms to fight viral infections such as HIV-1. A newly discovered innate immune defense to HIV-1 is the dNTP triphosphohydrolase enzyme SAMHD1. We are elucidating the enzymatic properties of this enzyme using the tools of structural biology, enzymology, synthetic chemistry, and cell biology. We ultimately seek to understand how SAMHD1 is involved in HIV-1 infectivity of immune cells.
Over the last decade fragment-based drug discovery has become a well-established approach for identifying lead compounds with pharmacologic activity. We have been exploring a substrate fragment-based approach for enzyme inhibitor design against several enzymes involved in uracil DNA base excision repair, which is an important pathway in viral pathogenesis, cancer chemotherapy and the development of lymphoid cancers. The approach relies on using a piece of the full substrate (the substrate fragment) that still binds competitively with the intact substrate to the active site. This substrate fragment can then be modified with a chemical handle to allow its connection via variable length linkers to a library of random molecular fragments. An efficient and economical chemical approach for assembly of substrate-fragment libraries is to use an aldehyde handle on the substrate fragment and bivalent alkyloxyamine linkers to link it to library aldehyde fragments via stable oxime linkages. Small molecule inhibitors of several enzymes (human uracil DNA glycosylase (hUNG), DNMT1, dUTPase) have been rapidly discovered in my lab using this approach.