Deluge synthesizes and screens novel DNA-encoded, one bead one compound (OBOC) libraries that are a source of ligands for difficult targets, including proteins that function via protein-protein interactions. (Fig. 1).1
Deluge libraries are comprised of linear and
macrocyclic PICCO molecules (peptoid-inspired
conformationally constrained oligomers, Fig. 2).2
PICCOs are able to engage shallow binding sites, such as protein-
protein interaction regions and allosteric sites, which
traditional drug molecules do poorly. PICCOs’
conformational constraints allow them to bind proteins with higher affinity.3-6
PICCOs are also highly cell permeable and stable to proteases.
Deluge OBOC libraries are screened using a novel FACS-based
technology that registers the selectivity of each molecule in the library, thus
favoring the isolation of highly selective ligands (Fig. 3).
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- Clark, M.A. et al. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nature Chem Biol 5, 647-654 (2009).
- MacConnell, A.B., McEnaney, P.J., Cavett, V.J. & Paegel, B.M. DNA-Encoded Solid-Phase Synthesis: Encoding Language Design and Complex Oligomer Library Synthesis. ACS Comb Sci 17, 518-534 (2015).
- Kodadek, T. & McEnaney, P.J. Towards vast libraries of scaffold-diverse, conformationally constrained oligomers. Chemical communications (Cambridge, England) 52, 6038-6059 (2016).
- Doran, T.M., Gao, Y., Simanski, S., McEnaney, P. & Kodadek, T. High affinity binding of conformationally constrained synthetic oligomers to an antigen-specific antibody: Discovery of a diagnostically useful synthetic ligand for murine Type 1 Diabetes autoantibodies. Bioorg. Med. Chem. Lett. 25, 4910-4917 (2015).
- Gao, Y. & Kodadek, T. Synthesis and screening of stereochemically diverse combinatorial libraries of peptide tertiary amides. Chem. & Biol. 20, 360-369 (2013).