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Discovery of Nucleic Acid Binding Molecules from Combinatorial Biohybrid Nucleobase Peptide Libraries

  • Sebastian Pomplun
    Sebastian Pomplun
    Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    More by Sebastian Pomplun
  • , 
  • Zachary P. Gates
    Zachary P. Gates
    Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    More by Zachary P. Gates
  • , 
  • Genwei Zhang
    Genwei Zhang
    Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    More by Genwei Zhang
  • , 
  • Anthony J. Quartararo
    Anthony J. Quartararo
    Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    More by Anthony J. Quartararo
  • , and 
  • Bradley L. Pentelute*
    Bradley L. Pentelute
    Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02142, United States
    Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States
    *[email protected]
    More by Bradley L. Pentelute
    Orcidhttp://orcid.org/0000-0002-7242-801X
Cite this: J. Am. Chem. Soc. 2020, 142, 46, 19642–19651
Publication Date (Web):November 9, 2020
https://doi.org/10.1021/jacs.0c08964
Copyright © 2020 American Chemical Society
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    Abstract

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    Nature has three biopolymers: oligonucleotides, polypeptides, and oligosaccharides. Each biopolymer has independent functions, but when needed, they form mixed assemblies for higher-order purposes, as in the case of ribosomal protein synthesis. Rather than forming large complexes to coordinate the role of different biopolymers, we dovetail protein amino acids and nucleobases into a single low molecular weight precision polyamide polymer. We established efficient chemical synthesis and de novo sequencing procedures and prepared combinatorial libraries with up to 100 million biohybrid molecules. This biohybrid material has a higher bulk affinity to oligonucleotides than peptides composed exclusively of canonical amino acids. Using affinity selection mass spectrometry, we discovered variants with a high affinity for pre-microRNA hairpins. Our platform points toward the development of high throughput discovery of sequence defined polymers with designer properties, such as oligonucleotide binding.

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    11. Jacob R. Immel, Steven Bloom. carba ‐Nucleopeptides ( c NPs): A Biopharmaceutical Modality Formed through Aqueous Rhodamine B Photoredox Catalysis. Angewandte Chemie International Edition 2022, 61 (28) https://doi.org/10.1002/anie.202205606
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    14. Li Quan Koh, Yi Wee Lim, Zachary P. Gates. Affinity Selection from Synthetic Peptide Libraries Enabled by De Novo MS/MS Sequencing. International Journal of Peptide Research and Therapeutics 2022, 28 (2) https://doi.org/10.1007/s10989-022-10370-9
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