Collaboration on DNA sequence-specific recognition by small molecules

随着人类基因组计划的完成，包括癌症、遗传性疾病和病毒性疾病在内的许多疾病都可以从DNA序列水平上理解。控制特定的基因表达将提供最终的基因治疗。基于核酸序列的识别，含有n -甲基吡咯和n -甲基咪唑氨基酸的小槽结合聚酰胺表现出良好的性能。各种类型的序列特异性DNA结合剂被开发并用于基因表达的调控。在本论文中，我们合成了新型聚酰胺-烷基化物和非天然DNA，并研究了包括吡咯-咪唑聚酰胺在内的小分子对序列特异性识别的分子基础。这些合成化合物选择性地烷基化预定的DNA序列，其中一些对某些癌细胞系具有选择性效力。提出了后基因组时代分子医学合理设计的未来方向之一。

By the completion of the human genome project, many diseases including cancer, hereditary and viral diseases can be understood by the DNA sequence level. Control of the specific gene expression will provide ultimate gene therapy. Minor groove binding polyamides containing N-methylpyrrole and N-methylimidazole amino acids exhibit promising performance based on the recognition of nucleic acid sequences. Various types of sequence-specific DNA binding agents are developed and used for the regulation of gene expression. In this collaboration, we synthesized novel type of polyamide-alkylator conjugates and unnatural DNA and investigated molecular basis of sequence specific recognition by small molecules including pyrrole-imidazole polyamides. These synthetic compounds alkylated predetermined DNA sequences selectively, and also some of them possessed selective potency for certain cancer cell lines. One of the future directions of rational design of molecular medicine in the post genome era is proposed.