Rivera-Sánchez María Del C, García-Arriaga Marilyn, Hobley Gerard, Morales-de-Echegaray Ana V, Rivera José M
Department of Chemistry and Molecular Sciences Research Center, University of Puerto Rico at Río Piedras, San Juan, Puerto Rico 00926, United States.
ACS Omega. 2017 Oct 31;2(10):6619-6627. doi: 10.1021/acsomega.7b01255. Epub 2017 Oct 11.
Most drugs are small molecules because of their attractive pharmacokinetics, manageable development and manufacturing, and effective binding into the concave crevices of bio-macromolecules. Despite these features, they often fall short when it comes to effectively recognizing the surfaces of bio-macromolecules. One way to overcome the challenge of biomolecular surface recognition is to develop small molecules that become self-assembled ligands (SALs) prior to binding. Herein, we report SALs made from 8-aryl-2'-deoxyguanosine derivatives forming precise hydrophilic supramolecular G-quadruplexes (SGQs) with excellent size, shape, and charge complementarity to G-quadruplex DNA (QDNA). We show that only those compounds forming SGQs act as SALs, which in turn differentially stabilize QDNAs from selected oncogene promoters and the human telomeric regions. Fluorescence resonance energy-transfer melting assays are consistent with spectroscopic, calorimetric, and light scattering studies, showing the formation of a "sandwichlike" complex QDNA·SGQ·QDNA. These results open the door for the advent of SALs that recognize QDNAs and potentially the surfaces of other bio-macromolecules such as proteins.
由于具有吸引人的药代动力学、易于管理的开发与制造过程以及能有效结合到生物大分子的凹形缝隙中，大多数药物都是小分子。尽管有这些特性，但在有效识别生物大分子表面方面，它们往往存在不足。克服生物分子表面识别挑战的一种方法是开发在结合前能自组装成配体（SALs）的小分子。在此，我们报告了由8-芳基-2'-脱氧鸟苷衍生物制成的SALs，它们能形成精确的亲水性超分子G-四链体（SGQs），与G-四链体DNA（QDNA）具有出色的尺寸、形状和电荷互补性。我们表明，只有那些形成SGQs的化合物才作为SALs起作用，进而对来自选定癌基因启动子和人类端粒区域的QDNAs产生不同程度的稳定作用。荧光共振能量转移熔解分析与光谱、量热和光散射研究结果一致，显示形成了“三明治样”复合物QDNA·SGQ·QDNA。这些结果为识别QDNAs以及可能识别其他生物大分子（如蛋白质）表面的SALs的出现打开了大门。
