Abiotic peptides as carriers of information for the encoding of small-molecule library synthesis
Name
nihms-1881119.pdf
Description
Accepted version
Size
1.7 MB
Format
Adobe PDF
Checksum (MD5)
645bf20fbad0f5afec519fb223620f60
Author(s)
Rössler, Simon L
Grob, Nathalie M
Buchwald, Stephen L
Pentelute, Bradley L
Date Issued
March 2, 2023
Journal
Science
Publisher
American Association for the Advancement of Science
Citation
Simon L. Rössler et al. ,Abiotic peptides as carriers of information for the encoding of small-molecule library synthesis. Science 379, 939-945( 2023).
Version
Author's final manuscript
Abstract
Encoding small-molecule information in DNA has been leveraged to accelerate the discovery of ligands for therapeutic targets such as proteins. However, oligonucleotide-based encoding is hampered by inherent limitations of information stability and density. In this study, we establish abiotic peptides for next-generation information storage and apply them for the encoding of diverse small-molecule synthesis. The chemical stability of the peptide-based tag allows the use of palladium-mediated reactions to efficiently synthesize peptide-encoded libraries (PELs) with broad chemical diversity and high purity. We demonstrate the successful de novo discovery of small-molecule protein ligands from PELs by affinity selection against carbonic anhydrase IX and the oncogenic protein targets BRD4(1) and MDM2. Collectively, this work establishes abiotic peptides as carriers of information for the encoding of small-molecule synthesis, leveraged herein for the discovery of protein ligands.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Broad Institute of MIT and Harvard
Terms of Use
Creative Commons Attribution-Noncommercial-ShareAlike
Persistent DSpace Link
DOI of Published Version
10.1126/science.adf1354
