title: Mapping polyamide-DNA interactions in human cells reveals a new design strategy for effective targeting of genomic sites.
abstract: Targeting the genome with sequence-specific synthetic molecules is a major goal at the interface of chemistry, biology, and personalized medicine. Pyrrole/imidazole-based polyamides can be rationally designed to target specific DNA sequences with exquisite precision in vitro; yet, the biological outcomes are often difficult to interpret using current models of binding energetics. To directly identify the binding sites of polyamides across the genome, we designed, synthesized, and tested polyamide derivatives that enabled covalent crosslinking and localization of polyamide-DNA interaction sites in live human cells. Bioinformatic analysis of the data reveals that clustered binding sites, spanning a broad range of affinities, best predict occupancy in cells. In contrast to the prevailing paradigm of targeting single high-affinity sites, our results point to a new design principle to deploy polyamides and perhaps other synthetic molecules to effectively target desired genomic sites in vivo.
authors: Department of Biochemistry and The Genome Center, University of Wisconsin - Madison, Madison, WI 53706 (USA).
authors: Graham S
authors: GS
authors: Erwin
authors: Devesh
authors: D
authors: Bhimsaria
authors: Asuka
authors: A
authors: Eguchi
authors: Aseem Z
authors: AZ
authors: Ansari
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D019295:Computational Biology; D004247:DNA / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D015195:Drug Design; D016678:Genome / Q000235:genetics*; D023281:Genomics; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D009757:Nylons; D004247:DNA
keywords: COSMIC; chemoinformatics; genome targeting; molecular recognition; polyamides