Oligonucleotide inhibitors of P-selectin-dependent neutrophil-platelet adhesion

被引:53
作者
Jenison, RD
Jennings, SD
Walker, DW
Bargatze, RF
Parma, D
机构
[1] NeXstar Pharmaceut Inc, Boulder, CO 80301 USA
[2] Montana Immunotech, Bozeman, MT 59717 USA
来源
ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT | 1998年 / 8卷 / 04期
关键词
D O I
10.1089/oli.1.1998.8.265
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
P-selectin, an inducible cell adhesion molecule, mediates rolling of neutrophils on activated vascular endothelium. Because rolling is an early event of the inflammatory response, therapeutic applications of selectin antagonists have been of broad interest. There are, however, no truly satisfactory therapeutic candidates among known inhibitors, Consequently, we have used Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technology, a process based on oligonucleotide combinatorial chemistry and in vitro selection, to develop aptamer antagonists of P-selectin, Equilibrium dissociation constants for aptamer/P-selectin binding range from 16 to 710 pM, a 10(5)-10(6)-fold improvement compared with the minimal carbohydrate ligand, sialyl Lewis X (sLe(X)). Aptamer binding is divalent cation dependent and, unlike sLeX, is specific for P-selectin, The selectivity for human P-selectin relative to human E-selectin or human L-selectin is 10(4)-10(5). In vitro, aptamers bind with subnanomolar affinities to P-selectin expressed on thrombin-activated platelets, inhibit the binding of P-selectin-IgG chimera to sLeX and to neutrophils, and block the binding activated platelets to neutrophils in flow cytometry and in hydrodynamic assays. Extrapolating from their in vitro characteristics, these novel P-selectin-specific antagonists may be suitable candidates for therapeutic development.
引用
收藏
页码:265 / 279
页数:15
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