ArticleProceedings of the National Academy of Sciences of the United States of America2022
Directed evolution identifies high-affinity cystine-knot peptide agonists and antagonists of Wnt/β-catenin signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 29 citations in OpenAlex.
- Tangled Tail of Mechanically Interlocked Peptides.Journal of the American Chemical Society · 2026Review
- Development of LRRC15-binding disulfide-constrained peptides for PET imaging of cancer-associated fibroblasts.Nature communications · 2026Article
- Selective and Potent Peptide Binders of RNF43 for Wnt Signaling Inhibition.ACS central science · 2025Article
- Advances in the development of Wnt/β-catenin signaling inhibitors.RSC medicinal chemistry · 2025Review
- Yeast as a tool for exploring disulfide-rich peptides.FEMS yeast research · 2025Review
- Ultra-High-Throughput Screening of Cystine-Rich Peptide Libraries Via Yeast Surface Display.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Selection of Nucleotide-Encoded Mass Libraries of Macrocyclic Peptides for Inaccessible Drug Targets.Chemical reviews · 2024Review
- Rapid prediction of key residues for foldability by machine learning model enables the design of highly functional libraries with hyperstable constrained peptide scaffolds.PLoS computational biology · 2024Article
- Triscysteine disulfide-directing motifs enabling design and discovery of multicyclic peptide binders.Nature communications · 2024Article
- Bioproduction Platform to Generate Functionalized Disulfide-Constrained Peptide Analogues.ACS bio & med chem Au · 2024Article
- Reconstitution of the alternative pathway of the complement system enables rapid delineation of the mechanism of action of novel inhibitors.The Journal of biological chemistry · 2024Article
- Cystine-knot peptide inhibitors of HTRA1 bind to a cryptic pocket within the active site region.Nature communications · 2024Article
- Strategies for the Construction of Multicyclic Phage Display Libraries.Chembiochem : a European journal of chemical biology · 2024Review
- An efficient mRNA display protocol yields potent bicyclic peptide inhibitors for FGFR3c: outperforming linear and monocyclic formats in affinity and stability.Chemical science · 2024Article
- Disulfide-constrained peptide scaffolds enable a robust peptide-therapeutic discovery platform.PloS one · 2024Article
- Toward reproducible tumor organoid culture: focusing on primary liver cancer.Frontiers in immunology · 2024Review
- A phage-displayed disulfide constrained peptide discovery platform yields novel human plasma protein binders.PloS one · 2024Article
- Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Directed evolution identifies high-affinity cystine-knot peptide agonists and antagonists of Wnt/β-catenin signaling.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Developing peptide-based tools to fine-tune growth signaling pathways, in particular molecules with exquisite selectivity and high affinities, opens up opportunities for cellular reprogramming in tissue regeneration. Here, we present a library based on cystine-knot peptides (CKPs) that incorporate multiple loops for randomization and selection via directed evolution. Resulting binders could be assembled into multimeric structures to fine-tune cellular signaling. An example is presented for the Wnt pathway, which plays a key role in the homeostasis and regeneration of tissues such as lung, skin, and intestine. We discovered picomolar affinity CKP agonists of the human LPR6 receptor by exploring the limits of the topological manipulation of LRP6 dimerization. Structural analyses revealed that the agonists bind at the first β-propeller domain of LRP6, mimicking the natural Wnt inhibitors DKK1 and SOST. However, the CKP agonists exhibit a different mode of action as they amplify the signaling of natural Wnt ligands but do not activate the pathway by themselves. In an alveolosphere organoid model, the CKP agonists induced alveolar stem cell activity. They also stimulated growth in primary human intestinal organoids. The approach described here advances the important frontier of next-generation agonist design and could be applied to other signaling pathways to discover tunable agonist ligands.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.