Selection for constrained peptides that bind to a single target protein
Name
s41467-021-26350-4.pdf
Description
Published version
Size
2.79 MB
Format
Adobe PDF
Checksum (MD5)
58a9fa817e0bee5b4c41a2175b2f7c28
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
Date Issued
2021
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
Abstract
AbstractPeptide 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 Escherichia coli 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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-021-26350-4
