The sequence specific recognition of double helical DNA is an essential biological process responsible for the regulation of cellular functions including transcription, replication, and cell division. The ability to design synthetic molecules that bind sequence specifically to unique sites on human DNA has major implications for the treatment of genetic, oncogenic and viral diseases. Basic research on structure-function issues such as recognition and covalent modification of DNA will be carried out. Research will focus on recognition of the minor groove of double helical DNA by a novel 2:1 peptide:DNA motif. Our specific objectives during the next four years are: (1) develop solid phase methods for the synthesis of oligopeptides containing imidazole and N-methylpyrrolecarboxamides. (2) define the sequence composition rules for recognition for the 2:1 peptide DNA motif by constructing and studying of the energetics of twenty-six different hairpin peptides. (3) define the upper limits for binding site size by the 2:1 motif. (4) design and study the energetics of binding of a novel class of alpha-amino acid linked imidazole-methylpyrrolecarboxamide peptides. (5) synthesize a class of rigid hairpin peptides and analyze the energetics for affinity and specificity. (6) synthesize a class of cyclic peptides and analyze the energetics for affinity and specificity. (7) develop a method for sequence specific DNA bending by the 2:1 DNA motif. (8) develop sequence specific ligation of double helical DNA promoted by minor groove binding prptides. In addition to the synthesis, specificity, and energetic studies at Caltech, all new synthetic peptides will be sent to UC Berkeley for structure elucidation of the peptide-DNA complexes by 2-D NMR.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM027681-17
Application #
2405222
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1980-04-01
Project End
2000-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
17
Fiscal Year
1997
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Engineering
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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Xu, Liang; Wang, Wei; Gotte, Deanna et al. (2016) RNA polymerase II senses obstruction in the DNA minor groove via a conserved sensor motif. Proc Natl Acad Sci U S A 113:12426-12431
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Hargrove, Amanda E; Raskatov, Jevgenij A; Meier, Jordan L et al. (2012) Characterization and solubilization of pyrrole-imidazole polyamide aggregates. J Med Chem 55:5425-32

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