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Selection for constrained peptides that bind to a single target protein

Author(s)
King, Andrew M; Anderson, Daniel A; Glassey, Emerson; Segall-Shapiro, Thomas H; Zhang, Zhengan; Niquille, David L; Embree, Amanda C; Pratt, Katelin; Williams, Thomas L; Gordon, D Benjamin; Voigt, Christopher A; ... Show more Show less
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Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/
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Abstract
<jats:title>Abstract</jats:title><jats:p>Peptide secondary metabolites are common in nature and have diverse pharmacologically-relevant functions, from antibiotics to cross-kingdom signaling. Here, we present a method to design large libraries of modified peptides in <jats:italic>Escherichia coli</jats:italic> and screen them in vivo to identify those that bind to a single target-of-interest. Constrained peptide scaffolds were produced using modified enzymes gleaned from microbial RiPP (ribosomally synthesized and post-translationally modified peptide) pathways and diversified to build large libraries. The binding of a RiPP to a protein target leads to the intein-catalyzed release of an RNA polymerase σ factor, which drives the expression of selectable markers. As a proof-of-concept, a selection was performed for binding to the SARS-CoV-2 Spike receptor binding domain. A 1625 Da constrained peptide (AMK-1057) was found that binds with similar affinity (990 ± 5 nM) as an ACE2-derived peptide. This demonstrates a generalizable method to identify constrained peptides that adhere to a single protein target, as a step towards “molecular glues” for therapeutics and diagnostics.</jats:p>
Date issued
2021
URI
https://hdl.handle.net/1721.1/147932
Department
Massachusetts Institute of Technology. Department of Biological Engineering
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
King, Andrew M, Anderson, Daniel A, Glassey, Emerson, Segall-Shapiro, Thomas H, Zhang, Zhengan et al. 2021. "Selection for constrained peptides that bind to a single target protein." Nature Communications, 12 (1).
Version: Final published version

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