Polyamides containing N-methylpyrrole and N-methylimidazole bind predetermined DNA sequences with affinity and specificity comparable to natural DNA binding proteins. They are cell permeable and able to inhibit gene transcription in vivo. Yet there is no report on how to use these polyamides to activate gene transcription. It is proposed here that FK506-linked polyamides are very likely to be able to target FKBP-VP16 transcription activation domain fusion protein (FKBPVP16) to DNA and activate gene transcription. Therefore, FK506-linked polyamide adapter molecules will be synthesized. Their ability to recruit FKBPVP16 to target DNA and transcription activity of the polyamide-FKBPVP16 complex will be tested in collaboration with Ron Prywes lab at Columbia University. Since dimerized transcription factors can bind longer DNA sequences with higher affinity than monomers, the difference between monomeric and dimeric artificial transcription factors in their transcriptional activity will be investigated. If this system works well, it will be the first example of artificial transcription factors that has the potential to activate the transcription of whatever gene, including the genes that play key roles in cancers. These artificial transcription factors will be powerful tools for biomedical research and have the potential to be used directly in gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM020336-02
Application #
6385125
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Ikeda, Richard A
Project Start
2001-06-01
Project End
Budget Start
2001-06-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$4,986
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Engineering
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125