Nucleic Acid Templated Reactions for Chemical Biology

Abstract

Nucleic acid directed bioorthogonal reactions offer the fascinating opportunity to unveil and redirect a plethora of intracellular mechanisms. Nano‐ to picomolar amounts of specific RNA molecules serve as templates and catalyze the selective formation of molecules that 1) exert biological effects, or 2) provide measurable signals for RNA detection. Turnover of reactants on the template is a valuable asset when concentrations of RNA templates are low. The idea is to use RNA‐templated reactions to fully control the biodistribution of drugs and to push the detection limits of DNA or RNA analytes to extraordinary sensitivities. Herein we review recent and instructive examples of conditional synthesis or release of compounds for in cellulo protein interference and intracellular nucleic acid imaging.

Templated chemistry for bioorganic synthesis and chemical biology

“…Most of the reactions pertinent to this idea belong to the category of cleavage reactions. Typically, bioactive molecules are released from inactive, prodrug‐like forms by some kind of dissociative chemistry such as hydrolysis, tetrazine‐mediated cleavage, reduction‐triggered fragmentation, or photoinduced cleavage . The aforementioned acyl transfer offers the prospect of building up drug‐like molecules by bond‐forming rather than bond‐cleaving reactions.…”

“…Typically, bioactive molecules are released from inactive, prodrug-like forms by some kind of dissociative chemistry such as hydrolysis, tetrazine-mediated cleavage, reduction-triggered fragmentation, or photoinduced cleavage. 16 The aforementioned acyl transfer offers the prospect of building up drug-like molecules by bond-forming rather than bond-cleaving reactions. The first example was described by Erben et al 106,107 The idea was to translate nucleic acid information into the output of peptide molecules that interfere with disease-related protein-protein interactions.…”

“…Templating can bring functional groups into proximity to direct or enable reactions that would otherwise not occur or at least not in a target‐specific fashion. Prominent examples can be found in nucleic acid directed chemistry where the sequence‐specific interactions between complementary oligonucleotides increase the effective molarity of functional groups and enable chemical reactions under dilute conditions where nontemplated biomolecular reactions cannot occur …”

“…Prominent examples can be found in nucleic acid directed chemistry where the sequence-specific interactions between complementary oligonucleotides increase the effective molarity of functional groups and enable chemical reactions under dilute conditions where nontemplated biomolecular reactions cannot occur. [16][17][18][19] Focusing on own work, this article intends to categorize and showcase different templating approaches used in bioorganic synthesis and chemical biology.…”

Turn On of a Ruthenium(II) Photocatalyst by DNA‐Templated Ligation

“…Oligonucleotides offer ap articularly attractive platform for templatedr eactionb ased on the fact that affinities of the supramolecular interactions are readily tunable, they can be multiplexed throughu nique oligonucleotide sequences and have important applications. [1][2][3][4] This has stimulateds ignificant efforts in the area, with agrowing number of reactions extending the breadtha nd scope of templated transformations. Prominent examples include nucleophilic reactions, [5][6][7] olefinations, [8][9] Staudinger reactions, [2,[10][11][12] conjugate additions, [13] native chemical ligations or acyl transfers, [14][15][16][17] and cycloadditions.…”