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Abstract：
DNA G-quadruplexes (G4s) form in relevant genomic regions and intervene in several biological processes, including the modulation of oncogenes expression, and are potential anticancer drug targets. The human KRAS proto-oncogene promoter region contains guanine-rich sequences able to fold into G4 structures. Here, by using circular dichroism and differential scanning calorimetry as complementary physicochemical methodologies, we compared the thermodynamic stability of the G4s formed by a shorter and a longer version of the KRAS promoter sequence, namely 5\'-AGGGCGGTGTGGGAATAGGGAA-3\' (KRAS 22RT) and 5\'-AGGGCGGTGTGGGAAGAGGGAAGAGGGGGAGG-3\' (KRAS 32R). Our results show that the unfolding mechanism of KRAS 32R is more complex than that of KRAS 22RT. The different thermodynamic stability is discussed based on the recently determined NMR structures. The binding properties of TMPyP4 and BRACO-19, two well-known G4-targeting anticancer compounds, to the KRAS G4s were also investigated. The present physicochemical study aims to help in choosing the best G4 target for potential anticancer drugs.
摘要：
DNAG-四体（G4s）在相关的基因组区域形成，并干预几个生物过程，包括癌基因表达的调节，是潜在的抗癌药物靶点。人KRAS原癌基因启动子区含有能够折叠成G4结构的富含鸟嘌呤的序列。这里,通过使用圆二色性和差示扫描量热法作为补充的物理化学方法，我们比较了由较短和较长版本的KRAS启动子序列形成的G4s的热力学稳定性，即5\'-AGGGCGGTGGGTGGGAATAGGGAA-3\'(KRAS22RT)和5\'-AGGGCGGGGGGAAGGGAAGGGAAGG-3\'(KRAS32R)。我们的结果表明，KRAS32R的展开机制比KRAS22RT的展开机制更复杂。根据最近确定的NMR结构讨论了不同的热力学稳定性。TMPyP4和BRACO-19，两个众所周知的G4靶向抗癌化合物的结合特性，对KRASG4s也进行了调查。本物理化学研究旨在帮助选择潜在抗癌药物的最佳G4靶标。
