Aptamers are short RNA or RNA-based polynucleotides that are designed to bind tightly and specifically to a target protein. They have engendered considerable excitement in recent years because of their potential uses as drugs, diagnostic probes, and research affinity agents. In fact, an aptamer that binds to vascular endothelial growth factor is now being used clinically to treat age-related macular degeneration, a leading cause of blindness in the elderly. However, RNA is readily degraded by RNases in vivo, greatly hindering the biomedical application of aptamers. This led Basic Sciences investigator Martin Egli and his collaborator Xianbin Yang at AM Biotechnologies to search for ways to improve the stability and affinity of aptamers. They discovered that a simple exchange of two atoms of oxygen for sulfur at a single position in the sugar-phosphate backbone of two different RNA aptamers markedly increased both the stability and the affinity of the molecules for their target proteins. In one case, the investigators showed that the modified aptamer, which labeled with a fluorescent tag, could detect a protein associated with cancer in cells expressing that protein. X-Ray crystallography revealed that the sulfur substitution increased binding affinity of one of the aptamers by increasing the molecule’s polarizability and ability to form hydrophobic contacts. If this approach can be generalized to other aptamers, it promises to markedly facilitate the development of new clinically useful aptamers in the future. The work is published in the journal Nucleic Acids Research [N. D. Abeydeera, et al. (2016) Nucleic Acids Res., 44, 8052 ].
Image attribution
Figure reproduced under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International license from Y. Zhao, et al. (2016), Cell Rep., 16, 2003.