Hirao I, Spingola M, Peabody D, Ellington A D
Department of Chemistry, University of Texas at Austin 78712, USA.
Mol Divers. 1998;4(2):75-89. doi: 10.1023/a:1026401917416.
It has been hypothesized that selections for aptamers with high affinity for a given target molecule will of necessity identify aptamers that have high specificity for that target. We have attempted to assess this hypothesis by selecting aptamers that can bind to MS2 coat protein or to single- or double-substitution variants of the coat protein. Some aptamers selected to bind MS2 coat protein or its variants were mildly specific for their cognate targets, discriminating by two- to fourfold against closely related proteins. Specificity determinants on both the coat proteins and the aptamers could be identified. However, many aptamers could readily bind to each of the different coat proteins. The identification of such aptamer 'generalists' belies the proposed relationship between the affinities and specificities of selected RNA ligands. These results imply that, while aptamers may not finely discriminate between closely related targets, neither will their binding be negated by mutations in targets. Aptamer pharmaceuticals may therefore better resist the evolution of resistance.
据推测，对给定靶分子具有高亲和力的适体的筛选必然会鉴定出对该靶标具有高特异性的适体。我们试图通过筛选能够结合MS2外壳蛋白或外壳蛋白的单取代或双取代变体的适体来评估这一假设。一些被选择结合MS2外壳蛋白或其变体的适体对其同源靶标具有一定的特异性，对密切相关的蛋白质的区分度为2至4倍。可以确定外壳蛋白和适体上的特异性决定因素。然而，许多适体能够轻松地结合每种不同的外壳蛋白。这种适体“通才”的鉴定与所选RNA配体的亲和力和特异性之间的假定关系相矛盾。这些结果表明，虽然适体可能无法在密切相关的靶标之间进行精细区分，但它们的结合也不会因靶标的突变而被否定。因此，适体药物可能更能抵抗耐药性的演变。
