title: 5-Hydroxymethyl-2'-deoxyuridine residues in the thrombin binding aptamer: investigating anticoagulant activity by making a tiny chemical modification.
abstract: We report an investigation into analogues of the thrombin binding aptamer (TBA). Individual thymidines were replaced by the unusual residue 5-hydroxymethyl-2'-deoxyuridine (hmU). This differs from the canonical thymidine by a hydroxyl group on the 5-methyl group. NMR and CD data clearly indicate that all TBA derivatives retain the ability to fold into the "chair-like" quadruplex structure. The presence of the hmU residue does not significantly affect the thermal stability of the modified aptamers compared to the parent, except for analogue H9, which showed a marked increase in melting temperature. Although all TBA analogues showed decreased affinities to thrombin, H3, H7, and H9 proved to have improved anticoagulant activities. Our data open up the possibility to enhance TBA biological properties, simply by introducing small chemical modifications.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli (Italy).
authors.forename: Antonella
authors.initials: A
authors.lastname: Virgilio
authors.forename: Luigi
authors.initials: L
authors.lastname: Petraccone
authors.forename: Maria
authors.initials: M
authors.lastname: Scuotto
authors.forename: Valentina
authors.initials: V
authors.lastname: Vellecco
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.forename: Luciano
authors.initials: L
authors.lastname: Mayol
authors.forename: Michela
authors.initials: M
authors.lastname: Varra
authors.forename: Veronica
authors.initials: V
authors.lastname: Esposito
authors.forename: Aldo
authors.initials: A
authors.lastname: Galeone
mesh_terms: D000925:Anticoagulants / Q000737:chemistry* / Q000378:metabolism; D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000378:metabolism; D001483:Base Sequence; D002942:Circular Dichroism; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D013917:Thrombin / Q000737:chemistry* / Q000378:metabolism; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000925:Anticoagulants; D052157:Aptamers, Nucleotide; C081676:thrombin aptamer; C018080:5-hydroxymethyl-2'-deoxyuridine; D005340:Fibrinogen; D013917:Thrombin; D013936:Thymidine
keywords: DNA structures; G-quadruplex; aptamer; hydroxymethyldeoxyuridine; inhibitors; thrombin binding aptamer