He G X, Williams J P, Postich M J, Swaminathan S, Shea R G, Terhorst T, Law V S, Mao C T, Sueoka C, Coutré S, Bischofberger N
Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, USA.
J Med Chem. 1998 Oct 22;41(22):4224-31. doi: 10.1021/jm970766i.
A series of 15-mer oligodeoxynucleotide analogues were synthesized, and their thrombin inhibitory activities in vitro and in vivo were evaluated. These oligodeoxynucleotide analogues share the same sequence (GGTTGGTGTGGTTGG) but have one or more phosphodiester linkages replaced by a neutral formacetal group. The results obtained from monosubstitutions show that no single phosphodiester group is critical for the thrombin inhibitory activity, suggesting that the interaction between the oligodeoxynucleotide and thrombin is based on a multiple-site charge-charge interaction. Analysis of the effects of different phosphodiester replacements indicates that the backside and left side of the chairlike structure formed by the molecule may be involved in binding with thrombin, presumably by having direct contacts with the anion-binding exosite of the enzyme. For the oligodeoxynucleotides containing two noncontiguous formacetal groups, the effect of the disubstitution is the sum of the effects obtained from the corresponding two monosubstitutions. Infusion of an oligodeoxynucleotide containing four formacetal groups into monkeys showed an increased in vivo anticoagulant effect and an extended in vivo half-life compared to the unmodified oligodeoxynucleotide.
合成了一系列15聚体寡脱氧核苷酸类似物，并评估了它们在体外和体内的凝血酶抑制活性。这些寡脱氧核苷酸类似物具有相同的序列（GGTTGGTGTGGTTGG），但有一个或多个磷酸二酯键被中性缩醛基团取代。单取代的结果表明，没有单个磷酸二酯基团对凝血酶抑制活性至关重要，这表明寡脱氧核苷酸与凝血酶之间的相互作用基于多位点的电荷-电荷相互作用。对不同磷酸二酯取代效果的分析表明，由该分子形成的椅状结构的背面和左侧可能参与与凝血酶的结合，推测是通过与该酶的阴离子结合外位点直接接触。对于含有两个不相邻缩醛基团的寡脱氧核苷酸，双取代的效果是相应两个单取代效果的总和。与未修饰的寡脱氧核苷酸相比，向猴子体内输注含有四个缩醛基团的寡脱氧核苷酸显示出体内抗凝效果增强和体内半衰期延长。
