Inhibition of gene transcription by polyamide DNA-binding ligands
AssigneesCalifornia Institute of Technology, The Scripps Research Institute
InventorsJoel M. Gottesfeld, Peter B. Dervan, Donald E. Mosier, Eldon E. Baird
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Abstract
The invention provides polyamides suitable for modulating cellular or viral gene expression by binding to an identified target DNA sequence adjacent to the binding site of a minor groove transcription factor protein. The polyamides of the present invention are useful for the treatment of a human infected with a virus such as HIV-1. The polyamides of the present invention are also useful for the treatment of conditions, such as cancers, that result from the expression or over-expression of cellular genes, particularly oncogenes.
Claims7
A method of inhibiting the replication of a pathogen by administering a transcription inhibiting amount of at least one polyamide compound having the form
- X1X2 . . . Xm-γ-X(m+1) . . . X(2m−1)X2m-β-Dp
- wherein X1, X2, XmX(m+1), X(2m−1), and X2m are carboxamide residues forming carboxamide binding pairs Xt/X2m, X2/X(2m−1), Xm/X(m+1), and γ is γ-aminobutyric acid or 2,4-diaminobutyric acid, β is β-alanine, and Dp is dimethylaminopropylamide, where m is an integer having a value from 3 to 6.
A method of inhibiting the replication of a pathogen by administering a transcription inhibiting amount of at least one polyamide
- wherein the polyamide is chosen from the group consisting of ImPyPyPy-γ-ImPyPyPy-β-Dp, ImPy-β-ImPy-γ-ImPy-β-ImPy-β-Dp, ImPy-β-PyPyPyPy-β-ImPy-β-Dp, ImPy-β-ImPy-β-PyPyPyPy-β-ImPy-β-ImPy-β-Dp, ImPy-β-ImPyPyPy-β-ImPyPyPy-β-PyPy-β-Dp, ImImPyPy-γ-ImPyPyPy-β-Dp, and mixtures thereof
- wherein Im is N-methylimidazole, Py is N-methylpyrrole, γ is γ-aminobutyric acid, β is β-alanine, and Dp is dimethylaminopropylamide.
A method of treating a human patient with an HIV-1 infection comprising the step of administering a composition comprising a transcription inhibiting amount of at least one polyamide chosen from the group consisting of ImPyPyPy-γ-ImPyPy-β-Dp, ImPy-β-ImPy-γ-ImPy-β-ImPy-β-Dp and mixtures thereof and a pharmaceutically acceptable excipient.
A method of treating HIV-1 infected human- blood cells in vitro comprising the step of administering a composition comprising a transcription inhibiting amount of at least one polyamide chosen from the group consisting of ImPyPyPy-γ-ImPyPy-β-Dp, ImPy-β-ImPy-γ-ImPy-β-ImPy-β-Dp and mixtures thereof.
Dependencies are inferred from the claim text.