ZT-65B, a hairpin polyamide that binds to the inverted CCAAT box (ICB) site of the human multidrug resistant (mdr1) gene: Design, DNA binding, and biological studies

ORGN 724

Zarmeen Taherbhai1, Suzanna Bailey1, Arden Sutterfield1, Karen Buchmueller, karen.buchmueller@furman.edu1, Binh Nguyen, chebkn@langate.gsu.edu2, Minal Kotecha3, Daniel Hochhauser3, John Hartley3, David Wilson2, and Moses Lee, Moses.Lee@furman.edu1. (1) Chemistry, Furman University, 3300 Poinsett Hwy, Greenville, SC 29613, (2) Department of Chemistry, Georgia State University, 50 Decatur St, Atlanta, GA 30303, (3) Oncology, Royal Free & London Medical SChool, London, United Kingdom
From the human genome project a number of relevant DNA targets have been identified, such as the inverted CCAAT boxes found in the mdr1 promoter. Binding of the nuclear transcriptional factor NF-Y (nuclear factor-Y) to the ICB sites up-regulates the expression of the mdr1 gene, leading to the onset of multi drug resistance in cancer chemotherapy. Using the rules of molecular recognition of DNA sequences by stacked polyamides, in which a Py/Py pair binds to either A/T or T/A, a Py/Im prefers a C/G, and an Im/Py recognizes a G/C, we have designed a hairpin polyamide, ZT-65B, to target the sequence 5'-TGGCT-3'. Introduced in ZT-65B is a potentially new DNA binding motif, and that is the 6-methylpicolinate/pyrrole pairing, which is expected to recognize a G/C base pair. In this presentation, the design of ZT-65B, its DNA binding to oligonucleotides containing the 5'-TGGCT sequence using DNA melting, CD titration and surface plasmon resonance (SPR) experiments, along with biological studies using DNase I footprinting and gel shift studies will be described.
 

Asymmetric Reactions, Molecular Recognition, Self Assembly, Bioorganic Chemistry, Process R&D
8:00 PM-10:00 PM, Wednesday, 16 March 2005 Convention Center -- Hall D, Poster

Division of Organic Chemistry

The 229th ACS National Meeting, in San Diego, CA, March 13-17, 2005