Selection for constrained peptides that bind to a single target protein

Andrew M. King, Daniel A. Anderson, Emerson Glassey, Thomas H. Segall-Shapiro, Zhengan Zhang, David L. Niquille, Amanda C. Embree, Katelin Pratt, Thomas L. Williams, D. Benjamin Gordon and Christopher A. Voigt ()
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Andrew M. King: Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology
Daniel A. Anderson: Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology
Emerson Glassey: Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology
Thomas H. Segall-Shapiro: Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology
Zhengan Zhang: Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology
David L. Niquille: Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology
Amanda C. Embree: Broad Institute of MIT and Harvard
Katelin Pratt: Broad Institute of MIT and Harvard
Thomas L. Williams: Broad Institute of MIT and Harvard
D. Benjamin Gordon: Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology
Christopher A. Voigt: Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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 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.

Date: 2021
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DOI: 10.1038/s41467-021-26350-4

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