Regulation of gene expression touches almost everything in eukaryotic biology and often generates drastic phenotypes in living organisms. Precise exogenous control of transcription by cell-permeable synthetic molecules represents a challenge in medicinal and bioorganic chemistry. Here we propose to develop cell-permeable organic compounds that mimic transcription factors. Naturally occurring transcription factors typically have two separable domains for binding specific DNA sequences and for activating transcription through protein-protein interactions. We plan to create artificial transcription factors by replacing these two polypeptide domains with synthetic molecules. As an activation module, a wrench-shaped molecule we named """"""""wrenchnolol"""""""" will be used, while a Dervan's hairpin polyamide molecule will be used as a DNA-binding module. The two cell-permeable modules will be coupled with each other at different positions and with different linkers, and the synthesized molecules will be assayed for their ability to activate transcription of a reporter gene in vitro, in cells, and in mice. We will also attempt to activate endogenous genes by synthetic transcription factors. We plan two approaches to achieving this challenging goal. In one, we will design and synthesize a synthetic molecule that mimics an endogenous transcription factor. As a proof of the concept, we plan to design a mimetic of MyoD, a transcription factor that induces myogenesis. In the other approach, a set of ten synthetic transcription factors will be designed in such a way that they synergistically activate transcription of a single gene. As a proof of the concept, we plan to activate the gene of VEGF-A, an endothelial cell-specific mitogen that is a key inducer of new blood vessel growth. ? ?
| Kwon, Youngjoo; Arndt, Hans-Dieter; Mao, Qian et al. (2004) Small molecule transcription factor mimic. J Am Chem Soc 126:15940-1 |
