Diversity-oriented synthesis encoded by deoxyoligonucleotides
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Published:2023-08-15
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Hudson LiamORCID, Mason Jeremy W., Westphal Matthias V.ORCID, Richter Matthieu J. R., Thielman Jonathan R.ORCID, Hua Bruce K.ORCID, Gerry Christopher J.ORCID, Xia GuoqinORCID, Osswald Heather L., Knapp John M., Tan Zher Yin, Kokkonda Praveen, Tresco Ben I. C., Liu ShuangORCID, Reidenbach Andrew G., Lim Katherine S.ORCID, Poirier Jennifer, Capece John, Bonazzi Simone, Gampe Christian M., Smith Nichola J.ORCID, Bradner James E.ORCID, Coley Connor W.ORCID, Clemons Paul A.ORCID, Melillo BrunoORCID, Hon C. Suk-Yee, Ottl Johannes, Dumelin Christoph E., Schaefer Jonas V.ORCID, Faust Ann Marie E.ORCID, Berst Frédéric, Schreiber Stuart L.ORCID, Zécri Frédéric J.ORCID, Briner Karin
Abstract
AbstractDiversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors and derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We also show screening results for three diverse protein targets. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference59 articles.
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