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Design of cyclic polyamides for sequence-specific recognition of the minor groove of DNA

Citation

Cho, Junhyeong (1996) Design of cyclic polyamides for sequence-specific recognition of the minor groove of DNA. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-04272006-161449

Abstract

NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document.

Small molecules that specifically bind with high affinity to any designated DNA sequence in the human genome would be useful tools in molecular biology and potentially in human medicine. Simple rules have been developed to rationally alter the sequence specificity of minor groove binding polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids. Crescent-shaped polyamides bind as antiparallel dimers with each polyamide making specific contacts with each strand on the floor of the minor groove.

In Chapter 2, the design of and synthesis of the cyclic polyamide cyclo-(Im-Py-Py-[...]-Py-Py-Py-[...]) is described. The cyclic polyamide binds the 5'-TGTTA-3' site with 40-fold higher affinity than the hairpin polyamide Im-Py-Py-[...]-Py-Py-Py-Dp. These results demonstrate that wholly designed synthetic cyclic polyamides with a molecular weight of 950 can bind designed five base pair sequences at subnanomolar concentration.

In Chapter 3, in order to develop polyamide ligands to differentiate between A,T-rich sequences, a cyclic polyamide has been synthesized in which two Py-Py-Py units are circled through two [...]-aminobutyric acids ([...]). DNase I footprinting titration experiments reveal that cyclo-(Py-Py-Py-[...]-Py-Py-Py-y) binds the 5'-TATAT-3' sequence with 20-fold higher affinity than distamycin.

In Chapter 4, experiments are described in which [...] is attached at unique sites of HIV-1 TAR RNA by the chemical synthesis method and autocleavage of [...] is performed. Preliminary results showed that the autocleavage pattern of TAR RNA is changed in the presence of arginine. However, a series of control experiments indicate that the change in the autocleavage pattern is not caused by an RNA conformational change driven by the binding of arginine.

Item Type:Thesis (Dissertation (Ph.D.))
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:
  • Unknown, Unknown
Defense Date:9 May 1996
Record Number:CaltechETD:etd-04272006-161449
Persistent URL:http://resolver.caltech.edu/CaltechETD:etd-04272006-161449
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1525
Collection:CaltechTHESIS
Deposited By: Imported from ETD-db
Deposited On:28 Apr 2006
Last Modified:26 Dec 2012 02:38

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