Department of Chemistry, Georgia State University, Atlanta, Georgia 30302-4098, United States.
J Am Chem Soc. 2012 Mar 21;134(11):5290-9. doi: 10.1021/ja211628j. Epub 2012 Mar 9.
Short AT base pair sequences that are separated by a small number of GCs are common in eukaryotic parasite genomes. Cell-permeable compounds that bind effectively and selectively to such sequences present an attractive therapeutic approach. Compounds with linked, one or two amidine-benzimidazole-phenyl (ABP) motifs were designed, synthesized, and evaluated for binding to adjacent AT sites by biosensor-surface plasmon resonance (SPR). A surprising feature of the linked ABP motifs is that a set of six similar compounds has three different minor groove binding modes with the target sequences. Compounds with one ABP bind independently to two separated AT sites. Unexpectedly, compounds with two ABP motifs can bind strongly either as monomers or as cooperative dimers to the full site. The results are supported by mass spectrometry and circular dichroism, and models to explain the different binding modes are presented.
短的 AT 碱基对序列，其被少数 GC 分隔，在真核寄生虫基因组中很常见。能够有效且选择性地结合到此类序列的细胞通透性化合物是一种有吸引力的治疗方法。设计、合成了具有连接的、一个或两个脒基-苯并咪唑-苯（ABP）基序的化合物，并通过生物传感器-表面等离子体共振（SPR）评估了它们与相邻 AT 位点的结合。连接的 ABP 基序的一个惊人特征是，一组六个类似的化合物具有三种不同的与靶序列的小沟结合模式。具有一个 ABP 的化合物独立地结合到两个分离的 AT 位点。出乎意料的是，具有两个 ABP 基序的化合物可以作为单体或以协同二聚体的形式强烈结合到完整的位点。质谱和圆二色性支持了这些结果，并提出了解释不同结合模式的模型。
