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Literature DB >> 25284901

Direct Ras Inhibitors Identified from a Structurally Rigidified Bicyclic Peptide Library.

Punit Upadhyaya¹, Ziqing Qian¹, Nurlaila A A Habir¹, Dehua Pei¹.

Abstract

A one-bead-two-compound (OBTC) library of structurally rigidified bicyclic peptides was chemically synthesized on TentaGel microbeads (90 μm), with each bead displaying a unique bicyclic peptide on its surface and a linear encoding peptide of the same sequence in its interior. Screening of the library against oncogenic K-Ras G12V mutant identified two classes of Ras ligands. The class I ligands apparently bind to the effector-binding site and inhibit the Ras-Raf interaction, whereas the class II ligand appears to bind to a yet unidentified site different from the effector-binding site. These Ras ligands provide useful research tools and may be further developed into therapeutic agents.

Entities: CellLine Chemical Disease Gene Mutation Species

Keywords: Bicyclic peptide; K-Ras; Protein-protein interaction; combinatorial library; inhibition

Year: 2014 PMID： 25284901 PMCID： PMC4180945 DOI： 10.1016/j.tet.2014.05.113

Source DB: PubMed Journal: Tetrahedron ISSN： 0040-4020 Impact factor: 2.457

35 in total

1. Sulindac-derived Ras pathway inhibitors target the Ras-Raf interaction and downstream effectors in the Ras pathway.

Authors: Herbert Waldmann; Ioanna-Maria Karaguni; Mercedes Carpintero; Eleni Gourzoulidou; Christian Herrmann; Christoph Brockmann; Hartmut Oschkinat; Oliver Müller
Journal: Angew Chem Int Ed Engl Date: 2004-01-16 Impact factor: 15.336

2. Homogeneous time-resolved fluorescence-based assay to screen for ligands targeting the growth hormone secretagogue receptor type 1a.

Authors: Jean-Philippe Leyris; Thomas Roux; Eric Trinquet; Pascal Verdié; Jean-Alain Fehrentz; Nadia Oueslati; Stéphanie Douzon; Emmanuel Bourrier; Laurent Lamarque; Didier Gagne; Jean-Claude Galleyrand; Céline M'kadmi; Jean Martinez; Sophie Mary; Jean-Louis Banères; Jacky Marie
Journal: Anal Biochem Date: 2010-09-24 Impact factor: 3.365

3. Myristoyl-based transport of peptides into living cells.

Authors: Allison R Nelson; Laura Borland; Nancy L Allbritton; Christopher E Sims
Journal: Biochemistry Date: 2007-11-29 Impact factor: 3.162

4. A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival.

Authors: Anurag Singh; Patricia Greninger; Daniel Rhodes; Louise Koopman; Sheila Violette; Nabeel Bardeesy; Jeff Settleman
Journal: Cancer Cell Date: 2009-06-02 Impact factor: 31.743

5. A new type of synthetic peptide library for identifying ligand-binding activity.

Authors: K S Lam; S E Salmon; E M Hersh; V J Hruby; W M Kazmierski; R J Knapp
Journal: Nature Date: 1991-11-07 Impact factor: 49.962

6. Single bead labeling method for combining confocal fluorescence on-bead screening and solution validation of tagged one-bead one-compound libraries.

Authors: Martin Hintersteiner; Thierry Kimmerlin; Frank Kalthoff; Markus Stoeckli; Geraldine Garavel; Jan-Marcus Seifert; Nicole-Claudia Meisner; Volker Uhl; Christof Buehler; Thomas Weidemann; Manfred Auer
Journal: Chem Biol Date: 2009-07-31

7. Traceless capping agent for peptide sequencing by partial edman degradation and mass spectrometry.

Authors: Amit Thakkar; Anne-Sophie Wavreille; Dehua Pei
Journal: Anal Chem Date: 2006-08-15 Impact factor: 6.986

8. N-methylation of peptides: a new perspective in medicinal chemistry.

Authors: Jayanta Chatterjee; Chaim Gilon; Amnon Hoffman; Horst Kessler
Journal: Acc Chem Res Date: 2008-07-18 Impact factor: 22.384

9. Efficient delivery of cyclic peptides into mammalian cells with short sequence motifs.

Authors: Ziqing Qian; Tao Liu; Yu-Yu Liu; Roger Briesewitz; Amy M Barrios; Sissy M Jhiang; Dehua Pei
Journal: ACS Chem Biol Date: 2012-11-12 Impact factor: 5.100

10. An orthosteric inhibitor of the Ras-Sos interaction.

Authors: Anupam Patgiri; Kamlesh K Yadav; Paramjit S Arora; Dafna Bar-Sagi
Journal: Nat Chem Biol Date: 2011-07-17 Impact factor: 15.040

11 in total

Review 1. Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view.

Authors: Shaoyong Lu; Hyunbum Jang; Shuo Gu; Jian Zhang; Ruth Nussinov
Journal: Chem Soc Rev Date: 2016-07-11 Impact factor: 54.564

Review 2. Targeting Ras with Macromolecules.

Authors: Dehua Pei; Kuangyu Chen; Hui Liao
Journal: Cold Spring Harb Perspect Med Date: 2018-03-01 Impact factor: 6.915

3. Binding hotspots on K-ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis.

Authors: Priyanka Prakash; John F Hancock; Alemayehu A Gorfe
Journal: Proteins Date: 2015-03-25

Direct Ras Inhibitors Identified from a Structurally Rigidified Bicyclic Peptide Library.

1. Sulindac-derived Ras pathway inhibitors target the Ras-Raf interaction and downstream effectors in the Ras pathway.

2. Homogeneous time-resolved fluorescence-based assay to screen for ligands targeting the growth hormone secretagogue receptor type 1a.

3. Myristoyl-based transport of peptides into living cells.

4. A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival.

5. A new type of synthetic peptide library for identifying ligand-binding activity.

6. Single bead labeling method for combining confocal fluorescence on-bead screening and solution validation of tagged one-bead one-compound libraries.

7. Traceless capping agent for peptide sequencing by partial edman degradation and mass spectrometry.

8. N-methylation of peptides: a new perspective in medicinal chemistry.

9. Efficient delivery of cyclic peptides into mammalian cells with short sequence motifs.

10. An orthosteric inhibitor of the Ras-Sos interaction.

Review 1. Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view.

Review 2. Targeting Ras with Macromolecules.

3. Binding hotspots on K-ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis.

Review 4. Bicyclic Peptides as Next-Generation Therapeutics.

Review 5. Macrocycles as protein-protein interaction inhibitors.

6. Inhibition of Ras signaling by blocking Ras-effector interactions with cyclic peptides.

7. Discovery of a Bicyclic Peptidyl Pan-Ras Inhibitor.

8. Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell-Permeable Bicyclic Peptides.

9. Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding.

10. Approaches to inhibiting oncogenic K-Ras.