title: Design, synthesis, and characterization of heparin-binding peptoids.
abstract: A series of N-substituted glycine oligomers (peptoids) of varying length and side chains was synthesized with the aim of producing peptidomimetics that would bind with high affinity to heparin and thereby neutralize its anticoagulant activity. To this end, a library of 29 peptoids was synthesized using solid phase synthesis methodologies. The general design of the peptoids was the repeating trimer sequence N(cationic side chain)-N(alkyl or benzyl side chain)-N(α-chiral side chain), where the monomers are N-substituted glycine residues bearing the indicated side chains. The peptoids were designed to have a helical structure with positively charged ammonium or guanidinium groups on side chains that would interact electrostatically with negatively charged sites on heparin. Binding of the peptoids by heparin was characterized by isothermal titration calorimetry (ITC) and heparin affinity chromatography (HAC). The secondary structure of the peptoids was characterized by circular dichroism (CD) spectroscopy. The peptoid design was systematically modified to produce peptoids with high affinity binding to heparin as measured by the above methods, resulting in the synthesis of peptoids with micromolar and sub-micromolar heparin-binding affinity. The efficacy of selected peptoids as agents for neutralization of the anticoagulant activity of heparin was assayed by the Coatest method, which measures restoration of the activity of the serine protease factor Xa (FXa). The results indicate that peptoids show promise as potential therapeutic agents for neutralization of the anticoagulant activity of heparin.
authors: Department of Chemistry, University of California Riverside , California 92521, United States.
authors: Bruce Kevin
authors: BK
authors: Ford
authors: Mark
authors: M
authors: Hamza
authors: Dallas L
authors: DL
authors: Rabenstein
mesh_terms: D000595:Amino Acid Sequence; D002151:Calorimetry; D002846:Chromatography, Affinity; D002942:Circular Dichroism; D006493:Heparin / Q000737:chemistry*; D008969:Molecular Sequence Data; D034444:Peptoids / Q000138:chemical synthesis / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D034444:Peptoids; D006493:Heparin