SBIR-STTR Award

(Adapted from investigator's abstract): The binding of transcription factor proteins to the promoter DNA is a crucial step in the control of gene expression. Gene expression is activated (or repressed) when the activation (or repression) domain of the transcription factor is tethered to the promoter through its DNA-binding domain. The main goal of Phase I of this project is to devise novel means for bringing the activation or repression domains to the promoter. Instead of using the DNA-binding domain, we will apply a novel methodology to accomplish the same effect. The crucial advantage of this method lies in the ability to expand the range of molecules that could be tested in transcriptional assays. This includes completely artificial, non-peptidic compounds. The long-term goal of this project is to develop new experimental strategies for screening the chemical combinatorial libraries for compounds that are active in transcriptional assays. Such molecules will have a significant pharmacological potential and will lead to a new class of drugs that target genes at the level of transcription.Proposed Commercial Application:Not available.

Thesaurus Terms:
gene induction /repression, genetic regulatory element, method development, transcription factor genetic promoter element, peptide, protein binding polymerase chain reaction

Regulation of gene expression by transcription factors is one of the most fundamental biological processes. The pharmaceutical manipulation of this process would open doors toward new approaches to treatment of cancer and other major diseases. We aim to develop a novel, comprehensive technology for manipulation of gene expression based on synthetic analogues of eukaryotic transcription factors. The design and synthesis of these artificial transcription factors (ATFs) has been accomplished in Phase I by replacing functional domains of natural transcription factors with artificial chemical moieties. These ATFs have a remarkably high biological activity combined with novel properties resulting from their unique chemical composition and structure. In Phase II we propose to develop ATF technology further and apply it to target selected human genes in their native, chromosomal setting in tissue culture cells. This will be achieved by using a combination of chemical, biochemical, genetic and genomic tools. The specific aims of this proposal are: 1) Expanding the repertoire of ATFs with new chemical moieties. 2) Developing a robust and rapid assay for testing of ATFs in human cell culture lines. 3) Demonstration of the ability of ATFs to target selected endogenous human genes in tissue culture.

Thesaurus Terms:
gene induction /repression, genetic regulatory element, method development, peptide chemical synthesis, synthetic protein, transcription factor genetic promoter element, peptide, protein binding, synthetic nucleic acid, transfection polymerase chain reaction