Dynamic Combinatorial Chemistry for Nucleic Acid Structures – DYCONAS

Non-canonical DNA and RNA structures, such as G-quadruplexes (G4) as well as hairpin-like, slipped-strand structures formed by tri-, tetra- and oligonucleotide repeats in DNA and RNA, represent therapeutically important targets whose biological functions can be modulated using small-molecule ligands. However, most known ligands, developed by rational design or combinatorial chemistry approaches, suffer from insufficient selectivity, in particular in terms of differentiation between structurally related targets (e.g., various G4-DNA and G4-RNA polymorphs; structurally similar RNA repeat structures). DYCONAS aims the development of a flexible dynamic combinatorial chemistry (DCC) methodology for target-guided discovery of novel, highly affine and selective ligands for non-canonical secondary structures of nucleic acids. The key feature of DYCONAS lies in the implementation of highly versatile acylhydrazone exchange chemistry for generation of dynamic combinatorial libraries that can be easily adapted to various DNA and RNA targets, covering a broad range of putative ligand structures. The perimeter of this project includes: (i) implementation, validation and optimization of the acylhydrazone-based DCC approach for nucleic acid targets; (ii) exploitation of this methodology for identification of novel potent ligands for therapeutically important nucleic acid targets, followed by a biophysical characterization of their interaction with the target in vitro; as well as (iii) exploration of acylhydrazone chemistry for the development of target-guided “in situ” synthesis of fluorescent or chromogenic ligands, aiming selective optical detection of nucleic acid targets.