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Design of sequence-specific DNA intercalators

Citation

Fechter, Eric James (2005) Design of sequence-specific DNA intercalators. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-06052005-164552

Abstract

Small molecules that bind specific DNA sequences may have powerful therapeutic applications by influencing the mechanisms of abnormal gene expression. Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) specifically bind the minor groove of DNA and have been shown to inhibit many protein-DNA complexes. However, some major groove-binding proteins can co-occupy the same DNA sequences as polyamides. Presented here are polyamide-intercalator conjugates that specifically bind target regions of DNA and deliver a non-specific intercalator to an adjacent site. The studies detail intercalative unwinding of specific DNA sequences to allosterically inhibit any protein:DNA complex. The evolution of sequence-specific polyamides to bisintercalate DNA and cause larger distortion of the helix is described. The success of hybrid molecules containing mixed DNA binding modes led to the development of a bis-polyamide-intercalator motif, modeled after the natural product actinomycin D, which is capable of specifically binding extended sequences of DNA. Also described is a polyamide-intercalator series which shows large fluorescence enhancement upon specific DNA binding and may be useful in detecting specific DNA sequences within living cells.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:intercalation; polyamide
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Dervan, Peter B.
Thesis Committee:
  • Rees, Douglas C. (chair)
  • Dougherty, Dennis A.
  • Dervan, Peter B.
  • Grubbs, Robert H.
Defense Date:31 May 2005
Author Email:fechter (AT) caltech.edu
Record Number:CaltechETD:etd-06052005-164552
Persistent URL:http://resolver.caltech.edu/CaltechETD:etd-06052005-164552
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:2456
Collection:CaltechTHESIS
Deposited By: Imported from ETD-db
Deposited On:05 Jun 2005
Last Modified:26 Dec 2012 02:51

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