The identification of nucleic acid ligands by the SELEX procedure has enjoyed considerable success over the past two decades. Nevertheless, chemical diversity of nucleic acids is more limited compared to that available in proteins and this has constrained the scope of targets for which high-quality nucleic acid ligands can be obtained. To bridge this gap in diversity, we have recently been using nucleic acid libraries with various functional groups introduced at the 5 position of deoxyuridine residues through amide linkages. For this purpose, we have assembled a library of modified nucleotides with moieties that mimic amino acid side chains and privileged fragments of small molecule drugs. Because base pairing is not compromised, such modifications are compatible with SELEX and can also be used for fully chemical post-SELEX optimization. A major benefit of using modified libraries of this type is a substantial increase in the number of targets accessible to SELEX including many proteins that have traditionally represented difficult targets. We have termed this new class of ligands slow off-rate modified aptamers, or SOMAmers, to account for their unique composition and binding properties. We have recently succeeded in obtaining high-resolution crystal structures for several SOMAmer protein complexes which have allowed us to gain an appreciation for the role modified nucleotides play in creating novel intramolecular motifs and shaping the protein-binding surfaces. Compared with conventional aptamers, SOMAmers engage their protein targets with interfaces that are notably more hydrophobic in character, thus expanding the range of epitopes available for binding. Overall, these advances to the SELEX method have allowed us to assemble a collection of over 1,100 SOMAmers to major protein families such as growth factors, cytokines, enzymes, hormones and receptors. This large and growing collection of affinity reagents has substantial potential for use in diagnostics and therapeutics.

Slow off-rate modified aptamers and their use as diagnostic and therapeutic agents

248th National Meeting (2014)

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