title: Design and synthesis of backbone cyclic phosphorylated peptides: The IkappaB model.
abstract: Phosphopeptides have been used to study phosphorylation and dephosphorylation, which are key events in protein expression. Backbone cyclization has been shown to increase the stability and selectivity of peptides. Backbone cyclic peptides with conformational diversity have produced bioactive peptides with improved pharmaceutical properties, metabolic stability, and enhanced intestinal permeability. We demonstrate a successful methodology for incorporating phospho-amino acids into backbone cyclic peptides. The nuclear factor-kappa B (NF-kappaB) is a latent mammalian protein prototype of dimeric transcription factors that exists in all cell types and plays a pivotal role in a huge number of genes, such as those responsible for chronic and acute inflammatory diseases. To inhibit NF-kappaB, backbone cyclic phosphopeptides were designed and synthesized based on the conserved sequence of the Inhibitor kappa B (IkappaB). The peptides were screened for inhibiting IkappaB ubiquitylation. The best compound showed 90% inhibition at a concentration of 3 microM, and its solution structure showed similarity to a related beta-catenin protein. This general methodology can be use for synthesizing cyclic phosphorylated, as well as backbone cyclic phosphorylated peptides for various biological targets.
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, The Hebrew University of Jerusalem, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Qvit
authors.forename: Ada
authors.initials: A
authors.lastname: Hatzubai
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Shalev
authors.forename: Assaf
authors.initials: A
authors.lastname: Friedler
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D017124:Conserved Sequence; D004330:Drosophila; D029721:Drosophila Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D029721:Drosophila Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010456:Peptides, Cyclic; D010748:Phosphopeptides; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase