title: DNA aptamers block L-selectin function in vivo. Inhibition of human lymphocyte trafficking in SCID mice.
abstract: Selectins participate in the initial events leading to leukocyte extravasation from the blood into tissues. Thus the selectins have generated much interest as targets for antiinflammatory agents. Therapeutic molecules based on the monomeric carbohydrate ligand sialyl Lewis X (SLe(X)) have low affinities and are not specific for a given selectin. Using SELEX (Systematic Evolution of Ligands by EXponential Enrichment) technology, we have generated aptamers specific for L-selectin that require divalent cations for binding and have low nanomolar affinity. In vitro, the deoxyoligonucleotides inhibit L-selectin binding to immobilized SLe(X) in static assays and inhibit L-selectin-mediated rolling of human lymphocytes and neutrophils on cytokine-activated endothelial cells in flow-based assays. These aptamers also block L-selectin-dependent lymphocyte trafficking in vivo, indicating their potential utility as therapeutics.
authors.affiliation: NeXstar Pharmaceuticals Inc., Boulder, Colorado 80301, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Hicke
authors.forename: S R
authors.initials: SR
authors.lastname: Watson
authors.forename: A
authors.initials: A
authors.lastname: Koenig
authors.forename: C K
authors.initials: CK
authors.lastname: Lynott
authors.forename: R F
authors.initials: RF
authors.lastname: Bargatze
authors.forename: Y F
authors.initials: YF
authors.lastname: Chang
authors.forename: S
authors.initials: S
authors.lastname: Ringquist
authors.forename: L
authors.initials: L
authors.lastname: Moon-McDermott
authors.forename: S
authors.initials: S
authors.lastname: Jennings
authors.forename: T
authors.initials: T
authors.lastname: Fitzwater
authors.forename: H L
authors.initials: HL
authors.lastname: Han
authors.forename: N
authors.initials: N
authors.lastname: Varki
authors.forename: I
authors.initials: I
authors.lastname: Albinana
authors.forename: M C
authors.initials: MC
authors.lastname: Willis
authors.forename: A
authors.initials: A
authors.lastname: Varki
authors.forename: D
authors.initials: D
authors.lastname: Parma
mesh_terms: D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D019041:L-Selectin / Q000378:metabolism*; D016256:Lewis X Antigen; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D011485:Protein Binding / Q000187:drug effects; D013050:Spectrometry, Fluorescence
chemical_list: D004268:DNA-Binding Proteins; D003854:Deoxyribonucleotides; D016256:Lewis X Antigen; D008024:Ligands; D019041:L-Selectin; D002118:Calcium