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Nat Chem DOI:10.1038/s41557-018-0033-8

Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules.

Publication TypeJournal Article
Year of Publication2018
AuthorsUsanov, DL, Chan, AI, Maianti, JPablo, Liu, DR
JournalNat Chem
Date Published2018 07
KeywordsCodon, DNA, Macrocyclic Compounds, Small Molecule Libraries, Stereoisomerism, Templates, Genetic

DNA-encoded libraries have emerged as a widely used resource for the discovery of bioactive small molecules, and offer substantial advantages compared with conventional small-molecule libraries. Here, we have developed and streamlined multiple fundamental aspects of DNA-encoded and DNA-templated library synthesis methodology, including computational identification and experimental validation of a 20 × 20 × 20 × 80 set of orthogonal codons, chemical and computational tools for enhancing the structural diversity and drug-likeness of library members, a highly efficient polymerase-mediated template library assembly strategy, and library isolation and purification methods. We have integrated these improved methods to produce a second-generation DNA-templated library of 256,000 small-molecule macrocycles with improved drug-like physical properties. In vitro selection of this library for insulin-degrading enzyme affinity resulted in novel insulin-degrading enzyme inhibitors, including one of unusual potency and novel macrocycle stereochemistry (IC = 40 nM). Collectively, these developments enable DNA-templated small-molecule libraries to serve as more powerful, accessible, streamlined and cost-effective tools for bioactive small-molecule discovery.


Alternate JournalNat Chem
PubMed ID29610462
PubMed Central IDPMC6014893
Grant List / / Howard Hughes Medical Institute / United States
R35 GM118062 / GM / NIGMS NIH HHS / United States