ArticleACS combinatorial science2016
Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell-Permeable Bicyclic Peptides.
Article in ACS combinatorial science, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 117 citations in OpenAlex.
- Phage Display Driven Identification and Computational Mapping of Macrocyclic Peptides Targeting RhoA G17V.Biochemistry · 2026Article
- Recent Advances in Peptide Inhibitors Targeting Wild-Type Ras Protein Interactions in Cancer Therapy.International journal of molecular sciences · 2025Review
- Unnatural Amino Acids: Strategies, Designs, and Applications in Medicinal Chemistry and Drug Discovery.Journal of medicinal chemistry · 2024Review
- Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics.Chemical reviews · 2024Review
- Design, synthesis, and analysis of macrobicyclic peptides for targeting the Gαi protein.Journal of peptide science : an official publication of the European Peptide Society · 2024Article
- KRAS4b:RAF-1 Homogenous Time-Resolved Fluorescence Resonance Energy Transfer Assay for Drug Discovery.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Bicyclic Peptide Library Screening for the Identification of Gαi Protein Modulators.Journal of medicinal chemistry · 2023Article
- Selected Approaches to Disrupting Protein-Protein Interactions within the MAPK/RAS Pathway.International journal of molecular sciences · 2023Review
- Targeting the 'Undruggable' Driver Protein, KRAS, in Epithelial Cancers: Current Perspective.Cells · 2023Review
- Inhibition ofPNAS nexus · 2023Article
- α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death.International journal of molecular sciences · 2023Article
- Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).Nature chemical biology · 2022Article
- Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds.Scientific reports · 2022Article
- Targeting Gαi/s Proteins with Peptidyl Nucleotide Exchange Modulators.ACS chemical biology · 2022Article
- Designing Cell-Permeable Peptide Therapeutics That Enter the Cell by Endocytosis.ACS symposium series. American Chemical Society · 2022Article
- MOrPH-PhD: A Phage Display System for the Functional Selection of Genetically Encoded Macrocyclic Peptides.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Utilization of macrocyclic peptides to target protein-protein interactions in cancer.Frontiers in oncology · 2022Review
- Discovery of a Bicyclic Peptidyl Pan-Ras Inhibitor.Journal of medicinal chemistry · 2021Article
- Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRASActa pharmaceutica Sinica. B · 2021Article
- Genetically-encoded discovery of proteolytically stable bicyclic inhibitors for morphogen NODAL.Chemical science · 2021Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Cyclic peptides have great potential as therapeutic agents and research tools. However, their applications against intracellular targets have been limited, because cyclic peptides are generally impermeable to the cell membrane. It was previously shown that fusion of cyclic peptides with a cyclic cell-penetrating peptide resulted in cell-permeable bicyclic peptides that are proteolytically stable and biologically active in cellular assays. In this work, we tested the generality of the bicyclic approach by synthesizing a combinatorial library of 5.7 × 10(6) bicyclic peptides featuring a degenerate sequence in the first ring and an invariant cell-penetrating peptide in the second ring. Screening of the library against oncoprotein K-Ras G12V followed by hit optimization produced a moderately potent and cell-permeable K-Ras inhibitor, which physically blocks the Ras-effector interactions in vitro, inhibits the signaling events downstream of Ras in cancer cells, and induces apoptosis of the cancer cells. Our approach should be generally applicable to developing cell-permeable bicyclic peptide inhibitors against other intracellular proteins.
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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 OpenQuestion graph.