Structural studies of the RNA aptamer drug, Macugen, bound to the angiogenic protein vascular endothelial growth factor

COMP 27

Arthur Pardi, arthur.pardi@colorado.edu1, Joon-Hwa Lee2, Fiona Jucker1, and Nicole K. Kruse1. (1) Department of Chemistry & Biochemistry, University of Colorado, Boulder, 215 UCB, Boulder, CO 80309, (2) Department of Chemistry, Gyeongsang National University, 900 Gajwa-dong, Jinju, Gyeongnam, 660-701, South Korea
Macugen is a 2'-fluoro pyrimidine RNA aptamer that binds with high affinity and specificity to a key regulator of angiogenesis, Vascular Endothelial Growth Factor, (VEGF). Macugen is approved for treatment of age related macular degeneration, which is the leading cause of blindness in the elderly. This aptamer binds specifically to the VEGF165 isoform, which is a dimeric protein with a receptor-binding domain and a heparin-binding domain (HBD). Binding experiments show that the HBD contributes the majority of the binding energy to the VEGF165-Macugen complex. NMR results will be presented which show that the structural features in the HBD-Macugen complex are also observed in the VEGF165-Macugen complex. The NMR solution structure of the HBD-Macugen complex will be presented, and structural studies on the full-length VEGF165-Macugen complex are in progress. These structural and biochemical data are being used to better understand the mechanism by which this RNA aptamer recognizes its target protein.
 

Protein-Nucleic Acid Interactions: Experimental and Modeling Analysis
8:30 AM-12:15 PM, Sunday, August 19, 2007 BCEC -- 156B, Oral

Division of Computers in Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007