Binding interactions between macromolecules are the main driving force behind transformations in biology.  Reagents capable of recognizing molecular targets with high affinity and specificity have numerous applications in chemistry, biology and medicine.  Since its discovery twenty-four years ago, SELEX (Systematic Evolution of Ligands by EXponential enrichment) has been a powerful tool for identifying nucleic acid-based ligands (aptamers) to a wide range of molecular targets.  The power of SELEX comes from extremely large libraries of randomized sequences (&gt;10<sup>15</sup>) that can be efficiently screened.  Nevertheless, identifying aptamers to certain protein targets has remained difficult, limiting the utility of the technology.  This is undoubtedly due to limitations in chemical diversity of nucleic acid compared to that of proteins. We have recently focused our attention on bridging this diversity gap by introducing functional groups that are absent in natural nucleic acid libraries, but often found in protein-protein interactions.  For this purpose, we have employed a versatile palladium-catalyzed carboxyamidation reaction to introduce functional groups at the 5-position of deoxyuridine, which do not disrupt base-pairing and are therefore compatible with the enzymatic steps of SELEX.   The use of such modified DNA libraries, in which only one out of four bases is uniformly modified, has made a profound impact on the success rate of SELEX, with hydrophobic aromatic moieties often resulting in best ligands.  We have named these ligands SOMAmers (Slow Off-rate Modified Aptamers).  Based on co-crystal structures of SOMAmer:protein complexes, it is clear that these modifications create entirely new structural motifs and generate extensive hydrophobic binding surfaces, in sharp contrast to mainly polar surfaces observed with conventional aptamers.  The expanded range of accessible epitopes on proteins has allowed us to build a collection of over 3,000 SOMAmers.  This set of binding reagents enables high-content proteomics, biomarker discovery and the development of novel diagnostic and therapeutic agents.

Modified aptamers and their uses in biomedical research and development

249th National Meeting (2015)

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