faboul@lsu.edu
BIOL 4596
- Biophysics of Macromolecules
In recent years, my aim has been the design of small molecule drugs aimed at disrupting RNA-protein interactions by binding to specific RNA structures. Pursuing this project in the pharmaceutical industry, we have targeted RNA structures relating to three diseases: 1) Human Immunodeficiency Virus (HIV) (the interaction of the Tat transcriptional activator protein with its target TAR RNA), 2) Hepatitis C Virus (HCV) (the Internal Ribosomal Entry Site (IRES), a complex folded secondary structure which sequesters host ribosomes for viral protein synthesis), and 3) antibiotic development (the bacterial ribosome). Although a number of clinically used antibiotics (such as neomycin, erythromycin, and chloramphenicol) target RNA, all of these are natural products, and structure-based drug design has yet to produce novel RNA-binding drugs.
I believe that there are two fundamental issues which need to be addressed to facilitate RNA structure-based drug design: the extraordinary conformational flexibility of RNA and the requirement for exploring novel regions of chemical space.
In my lab I hope to address these two issues by studying the phenomena of recently discovered “riboswitches”. These are RNA secondary structures which regulate transcription and/or translation in bacteria in response to interaction with small molecule metabolites, such as B vitamins, amino acids and their derivatives (including lysine, S-adenosyl methionine, and glycine), and nucleotides. The discovery of these systems sheds light upon the “RNA world” hypothesis and the role of RNA in the origin of life. At the same time, riboswitches demonstrate that a small, drug-like molecule can act to control critical biological processes in a pathogen by acting at the RNA level.
My lab will use physical techniques including Nuclear Magnetic Resonance (NMR) to study the coupling between small molecule binding and RNA conformational flexibility in riboswitches, and design special small molecule “fragment” libraries to search for new ligands for these RNAs, as well as for RNAs of therapeutic interest such as the viral and bacterial targets mentioned. In this way, we hope to address the two fundamental issues pertinent to drug design.
Selected Publications
Lentzen, G., Klinck, R., Matassova, N., Aboul-ela, F., and Murchie, A. I. H. 2003. Structural basis for contrasting activities of ribosome-binding thiazole antibiotics. Chemistry & Biology. 10(8): 769-778.
Davis, B., Afshar, M., Varani, G., Murchie, A. I. H., Karn, J., Lentzen, G, Drysdale, M. J., Bower, J., Potter, A. J., Starkey, I. D., Swarbrick, T. M., and Aboul-ela, F. 2004. Moulding RNA conformation by stabilisation of electrostatic "hot spots"; how ligand-induced conformational change in RNA mediates specific interaction. Journal of Molecular Biology. 336: 343-356.
Murchie, A. I. H., Davis, B., Isel, C., Afshar, M., Drysdale, M. J., Bower, J., Potter, A. J., Starkey, I. D., Swarbrick, T. M., Mirza, S., Prescott, C. D., Vaglio, P., Aboul-ela, F., and Karn, J. 2004. Structure-based drug design targeting an inactive conformation: exploiting the flexibility of HIV-1 TAR RNA Journal of Molecular Biology. 336: 625-638.
Baurin N, Aboul-Ela F, Barril X, Davis B, Drysdale M, Dymock B, Finch H, Fromont C, Richardson C, Simmonite H, Hubbard RE. 2004. Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets. J Chem Inf Comput Sci. 44(6): 2157-66.
François, B., Russell, R., Murray, J., Aboul-ela, F., Masquida, B., Vicens, Q. & _Westhof, E._ (2005). Crystal structures of complexes between aminoglycosides and decoding A-site oligonucleotides: Role of the number of rings and positive charges in the specific binding leading to miscoding. /Nucleic Acids Res/ *33*, 5677-5690.
Foloppe, N., Matassova, N. & _Aboul-ela, F._ (2006). Towards the discovery of drug-like RNA ligands? /Drug Discovery Today/ *11*, 1019-1027.