Robert Wood Johnson Medical School
Dept. of Pharmacology
RWJMS. Room 422
Piscataway, NJ 08854
Development of topoisomerase I-directed anticancer drugs, investigations of the structure and energetics of drug-RNA interactions
The DNA topoisomerases have been established as effective molecular targets for anticancer drugs. Interest in topoisomerase I (TOP1) as a new molecular target for anticancer drugs has stimulated the search for new TOP1 inhibitors. This search has led to the identification of numerous new TOP1-inhibiting compounds. However, despite the increasing number of TOP1 inhibitors, our current understanding of the molecular mechanism(s) underlying TOP1 inhibition is still quite limited, a deficiency that hinders our ability to design new compounds with desired TOP1 inhibiting and tumor cell killing activities. To address this deficiency, the primary goal of this research program is to understand the molecular mechanism by which DNA-binding drugs stimulate human DNA TOP1-Mediated DNA damage (cleavage).X-ray crystal structure of reconstituted human DNA topoisomerase I in covalent complex with a DNA duplex. The active-site tyrosine residue that it covalently attached to the DNA is shown in a blue space-filling model.
Investigations of the Structure and Energetics of Drug-RNA Interactions
RNA can fold into a variety of different structures and/or conformations that can serve as specific recognition elements for drugs. Targeting these structural RNA elements in a site-specific manner offers the potential for modulating the biological function of the targeted RNA. To date, little is known about the thermodynamic driving forces that dictate, control, and stabilize drug-RNA interactions, a deficiency that limits our ability to design new agents with predictable RNA binding affinities and specificities over a range of solution conditions. The primary goal of this research program is to define the rules that govern the affinities and specificities of drugs for their RNA targets. Specifically, we are defining the relative contributions of van der Waals contacts, hydrogen bonding, and electrostatic interactions to the binding affinities and specificities of RNA-directed ligands. We also are evaluating how the presence and sequence of loops and bulges in the host RNA modulate drug recognition. Currently, our studies are focused on targeting various bacterial, viral, and group I intron RNA sequences.
NMR-derived solution structure of the complex formed between the aminoglycoside antibiotic, paromomycin, and an oligonucleotide that models the A-site of the 16S rRNA subunit. The drug is depicted as a space-filling model.