[A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165 ]
>>Published online before print December 15, 2005
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0509069102
A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165
( age-related macular degeneration | Macugen | RNA | NMR )
Joon-Hwa Lee *, Marella D. Canny *, Andrea De Erkenez , Dominik Krilleke , Yin-Shan Ng , David T. Shima , Arthur Pardi *, and Fiona Jucker *
*Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309; and Eyetech Research Center, Lexington, MA 02421
Communicated by Larry Gold, SomaLogic, Inc., Boulder, CO, October 20, 2005 (received for review August 29, 2005)
Aptamers recognize their targets with extraordinary affinity and specificity. The aptamer-based therapeutic, Macugen, is derived from a modified 2'fluoro pyrimidine RNA inhibitor to vascular endothelial growth factor (VEGF) and is now being used to treat the wet form of age-related macular degeneration. This VEGF165 aptamer binds specifically to the VEGF165 isoform, a dimeric protein with a receptor-binding domain and a heparin-binding domain (HBD). To understand the molecular recognition between VEGF and this aptamer, binding experiments were used to show that the HBD contributes the majority of binding energy in the VEGF165-aptamer complex. A tissue culture-based competition assay demonstrated that the HBD effectively competes with VEGF165 for aptamer binding in vivo. Comparison of NMR spectra revealed that structural features of the smaller HBD-aptamer complex are present in the full-length VEGF164-aptamer complex. These data show that the HBD provides the binding site for the aptamer and is the primary determinant for the affinity and specificity in the VEGF165-aptamer complex.<<
Doubt this really helps in any major sense, but what the heck?
Cheers, Tuck |
