Chemically modified oligonucleotides (CMOs) are widely explored as antisense, siRNA and aptamer candidates for therapeutic applications. CMO-based therapeutics offer considerable potential in silencing ‘non-druggable’ targets that are not amenable to more conventional approaches employing small molecules, proteins, or monoclonal antibodies. Numerous modifications involving backbone and/or bases as well as oligonucleotide-conjugates have been assessed in regard to the effects of modification on target affinity, nuclease resistance, cellular uptake, biodistribution, and efficacy. We have used crystal structures of CMOs to better understand the consequences of modifications for conformation, pairing preferences and nuclease stability for over 20 years. However, despite hundreds of CMO structures and thousands of structures of complexes between proteins and native nucleic acids deposited in the Protein Data Bank (www.rcsb.org), only a limited number of structural investigations directed at CMO-protein interactions have been conducted in the antisense, siRNA or aptamer contexts. As a result, our understanding at the 3D-structural level of how modifications change protein binding, affinity (aptamer-protein interactions), or processing of RNA targets by key players in the antisense (RNase H) or RNAi (Ago2) pathways is rather poor. To address this void we have initiated crystallographic investigations of complexes between proteins and chemically modified siRNAs or aptamers.

Structure-based insights into stability, activity and protein interactions of chemically modified oligonucleotides

253rd National Meeting (2017)

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