Nucleic acids, DNA and RNA, are most widely recognized for their genetic role. Recent research has identified additional roles in biology, medicine and directed assembly of materials. To mitigate the challenges of native nucleic acids, analogues with non-natural backbones have been designed though each suffers from similar synthetic challenges to native nucleic acids.<br/>By utilizing thiol-click reactions, particularly the radical thiol-ene addition, we have developed nucleic acid analogues, designated CNAs for “Click Nucleic Acid,” with sulfur-containing backbone polymers, that bind with complementary sequences of single stranded DNA with high specificity. These uncharged backbones permit hybridization without charge shielding and the oligomers are not susceptible to degradation via the same physiological mechanisms as native nucleic acids. Furthermore, in contrast to the solid phase synthesis of nucleic acids and their analogues, which may require as much as one hour per residue, CNAs can be synthesized from monomers in less than one minute. Additionally, solution phase synthesis allows for easily scalable synthesis that is not subject to the surface area constraints of heterogenous solid phase-supported reactions.<br/>Such CNAs can be grafted to or grafted on synthetic and natural polymers to create a variety of block copolymer architectures which can subsequently assemble into higher order structures. Taking advantage of the intermolecular interactions of nucleobases, this approach has allowed us to generate drug-loaded block copolymer nanoparticles and physically crosslinked gels that assemble via sequence specific CNA-DNA interaction. Copolymers of CNAs are also capable of rapid cell uptake, portending applications in the delivery of tethered payloads. In summary, in addition to addressing the challenges of alternative nucleic acid and nucleic acid analog syntheses and application, employment of thiol-click reactions for the synthesis of CNAs generates new potential for custom macromolecular and materials design.

Nucleic acid analogs via thiol-click reactions

256th National Meeting (2018)

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