Selection for constrained peptides that bind to a single target protein
| Autor: | Daniel A. Anderson, Amanda C. Embree, Thomas Williams, Andrew M. King, David L. Niquille, Christopher A. Voigt, Thomas H. Segall-Shapiro, Zhengan Zhang, Katelin Pratt, Emerson Glassey, D. Benjamin Gordon |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Science Drug Evaluation Preclinical General Physics and Astronomy Peptide Plasma protein binding medicine.disease_cause Antiviral Agents General Biochemistry Genetics and Molecular Biology Article Synthetic biology chemistry.chemical_compound RNA polymerase medicine Humans Escherichia coli Selectable marker chemistry.chemical_classification Multidisciplinary SARS-CoV-2 COVID-19 General Chemistry COVID-19 Drug Treatment Kinetics Enzyme chemistry Biochemistry Drug Design Spike Glycoprotein Coronavirus Natural product synthesis Target protein Peptides human activities Protein Binding |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) |
| ISSN: | 2041-1723 |
| Popis: | 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. Peptide secondary metabolites have a diverse range of functions. Here the authors present a method to design and screen a large library of modified peptides in E. coli against a target of interest. |
| Databáze: | OpenAIRE |
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