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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 Jul

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