Dickinson L A, Gulizia R J, Trauger J W, Baird E E, Mosier D E, Gottesfeld J M, Dervan P B
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12890-5. doi: 10.1073/pnas.95.22.12890.
Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis. Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the transcription factors Ets-1, lymphoid-enhancer binding factor 1, and TATA-box binding protein. These synthetic ligands specifically inhibit DNA-binding of each transcription factor and HIV type 1 transcription in cell-free assays. When used in combination, the polyamides inhibit virus replication by >99% in isolated human peripheral blood lymphocytes, with no detectable cell toxicity. The ability of small molecules to target predetermined DNA sequences located within RNA polymerase II promoters suggests a general approach for regulation of gene expression, as well as a mechanism for the inhibition of viral replication.
能够穿透人体细胞的序列特异性DNA结合小分子有可能调节特定基因的转录。1型人类免疫缺陷病毒（HIV-1）进行RNA合成需要多种细胞DNA结合转录因子。设计了两种吡咯-咪唑聚酰胺，使其结合与转录因子Ets-1、淋巴样增强子结合因子1和TATA盒结合蛋白的结合位点紧邻的DNA序列。在无细胞试验中，这些合成配体特异性抑制每种转录因子的DNA结合以及HIV-1转录。联合使用时，聚酰胺在分离的人外周血淋巴细胞中抑制病毒复制的效率>99%，且未检测到细胞毒性。小分子靶向位于RNA聚合酶II启动子内的预定DNA序列的能力提示了一种调节基因表达的通用方法，以及一种抑制病毒复制的机制。
