Targeting Nucleic Acids using Dynamic Combinatorial Chemistry

Abstract

Dynamic combinatorial chemistry (DCC) is a powerful method for the identification of novel ligands for the molecular recognition of receptor molecules. The method relies on self-assembly processes to generate libraries of compounds under reversible conditions, allowing a receptor molecule to select the optimal binding ligand from the mixture. However, while DCC is now an established field of chemistry, there are limited examples of the application of DCC to nucleic acids. The requirement to conduct experiments under physiologically relevant conditions, and avoid reaction with, or denaturation of, the target nucleic acid secondary structure, limits the choice of the reversible chemistry, and presents restrictions on the building block design. This review will summarize recent examples of applications of DCC to the recognition of nucleic acids. Studies with duplex DNA, quadruplex DNA, and RNA have utilized mainly thiol disulfide libraries, although applications of imine libraries, in combination with metal coordination, have been reported. The use of thiol disulfide libraries produces lead compounds with limited biostability, and hence design of stable analogues or mimics is required for many applications.

Direct Observation of Intermediates in a Thermodynamically Controlled Solid-State Dynamic Covalent Reaction

“…DCC provides an approach to the discovery of complex architectures and receptors that may be inaccessible or unimaginable by rational design . It also has potential applications in a wide range of chemical and biological problems that involve binding equilibria in chemistry and biology. , The members of a dynamic combinatorial library (DCL) are molecules that form in a combinatorial way by linking building blocks together through reversible covalent bonds that are dynamic, being continuously broken and re-formed. The concentration of each library member is dictated by its relative free energy; therefore, any phenomenon that can affect the stability of one or more DCL members will affect the concentration of all the library members in the DCL and therefore the overall DCL composition.…”