Diversity-oriented synthesis encoded by deoxyoligonucleotides

Liam Hudson, Jeremy W. Mason, Matthias V. Westphal, Matthieu J. R. Richter, Jonathan R. Thielman, Bruce K. Hua, Christopher J. Gerry, Guoqin Xia, Heather L. Osswald, John M. Knapp, Zher Yin Tan, Praveen Kokkonda, Ben I. C. Tresco, Shuang Liu, Andrew G. Reidenbach, Katherine S. Lim, Jennifer Poirier, John Capece, Simone Bonazzi, Christian M. Gampe, Nichola J. Smith, James E. Bradner, Connor W. Coley, Paul A. Clemons, Bruno Melillo, C. Suk-Yee Hon, Johannes Ottl, Christoph E. Dumelin, Jonas V. Schaefer, Ann Marie E. Faust, Frédéric Berst, Stuart L. Schreiber, Frédéric J. Zécri () and Karin Briner
Additional contact information
Liam Hudson: Chemical Biology and Therapeutics Science Program, Broad Institute
Jeremy W. Mason: Chemical Biology and Therapeutics Science Program, Broad Institute
Matthias V. Westphal: Chemical Biology and Therapeutics Science Program, Broad Institute
Matthieu J. R. Richter: Chemical Biology and Therapeutics Science Program, Broad Institute
Jonathan R. Thielman: Chemical Biology and Therapeutics Science Program, Broad Institute
Bruce K. Hua: Chemical Biology and Therapeutics Science Program, Broad Institute
Christopher J. Gerry: Chemical Biology and Therapeutics Science Program, Broad Institute
Guoqin Xia: The Scripps Research Institute
Heather L. Osswald: The Scripps Research Institute
John M. Knapp: Chemical Biology and Therapeutics Science Program, Broad Institute
Zher Yin Tan: Chemical Biology and Therapeutics Science Program, Broad Institute
Praveen Kokkonda: Chemical Biology and Therapeutics Science Program, Broad Institute
Ben I. C. Tresco: Chemical Biology and Therapeutics Science Program, Broad Institute
Shuang Liu: Chemical Biology and Therapeutics Science Program, Broad Institute
Andrew G. Reidenbach: Chemical Biology and Therapeutics Science Program, Broad Institute
Katherine S. Lim: Chemical Biology and Therapeutics Science Program, Broad Institute
Jennifer Poirier: Novartis Institutes for BioMedical Research
John Capece: Novartis Institutes for BioMedical Research
Simone Bonazzi: Novartis Institutes for BioMedical Research
Christian M. Gampe: Novartis Institutes for BioMedical Research
Nichola J. Smith: Novartis Institutes for BioMedical Research
James E. Bradner: Novartis Institutes for BioMedical Research
Connor W. Coley: Chemical Biology and Therapeutics Science Program, Broad Institute
Paul A. Clemons: Chemical Biology and Therapeutics Science Program, Broad Institute
Bruno Melillo: The Scripps Research Institute
C. Suk-Yee Hon: Chemical Biology and Therapeutics Science Program, Broad Institute
Johannes Ottl: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus
Christoph E. Dumelin: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus
Jonas V. Schaefer: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus
Ann Marie E. Faust: Novartis Institutes for BioMedical Research
Frédéric Berst: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus
Stuart L. Schreiber: Chemical Biology and Therapeutics Science Program, Broad Institute
Frédéric J. Zécri: Novartis Institutes for BioMedical Research
Karin Briner: Novartis Institutes for BioMedical Research

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Diversity-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.

Date: 2023
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DOI: 10.1038/s41467-023-40575-5

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