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US 6,958,240 B1Granted
Inhibition of major groove DNA binding proteins by modified polyamides
AssigneeCalifornia Instiute of Technology
InventorsEldon E. Baird, Peter B. Dervan
Life of this patent
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Abstract
This invention provides improved polyamides comprising a positive patch for contacting the phosphate backbone or major groove of a DNA molecule. As such, the improved polyamides are capable of inhibiting the function or binding of a DNA-binding protein to a DNA molecule. The improved polyamide provides for more efficient function of the polyamide.
Claims25
A polyamide molecule that specifically binds to base pairs in the minor groove of a DNA molecule, said polyamide molecule comprising:
- one or more amino acids comprising a moiety selected from the group consisting of N-methylpyrrole, 3-hydroxy-N-methylpyrrole, and N-methylimidazole, wherein one or more of said amino acid(s) are not α-amino acids;
- and
- a positive patch consisting of a rigid group adjacent to a positively charged group, said rigid group comprising a first and a second amino acid;
- said first amino acid being selected from the group consisting of arginine, proline, lysine, and hydroxyproline;
- and said second amino acid being selected from the group consisting of proline, glycine, serine, threonine, leucine, isoleucine, valine, alanine, and hydroxyproline.
2 more elements
A tandem-linked polyamide having the formula:
- wherein γ is —NH—CH2—CH2—CH2—CONH— hairpin linkage derived from γ-aminobutyric acid or a chiral hairpin linkage derived from 2,4-diaminobutyric acid;
- X1/X6, X2/X5, X3/X4, X′1/X′6, X′2/X′5, and X′3/X′4 represent carboxamide binding pairs which bind DNA base pairs and are selected from the group consisting of Hp/Py, Py/Hp, Py/Im, Im/Py, and Py/Py to correspond to the DNA base pair in the minor groove to be bound;
- L represents an amino acid linking group selected from the group consisting of β-alanine and 5-aminovaleric acid (δ);
- P represents a polyamide selected from the group consisting of X1X2X3γX4X5X6, X1X2X3X4γX5X6X7X8, X1X2X3X4X5γX6X7X8X9X10, and X1X2X3X4X5X6γX7X8X9X10X11X12, where X1-X12 are independently selected from the group consisting of β-alanine, pyrrole, hydroxypyrrole and imidazole;
- and
- A represents a positive patch consisting of a rigid group adjacent to a positively charged group.
3 more elements
A tandem-linked polyamide having the formula:
- wherein γ is —NH—CH2—CH2—CH2—CONH— hairpin linkage derived from γ aminobutyric acid or a chiral hairpin linkage derived from 2,4-diaminobutyric acid;
- X1/X8, X2/X7, X3/X6, X4/X5, X′1/X′8, X′2/X′7, X′3/X′6, and X′4/X′5, represent carboxamide binding pairs which bind DNA base pairs and are selected from the group consisting of Hp/Py, Py/Hp, Py/Im, Im/Py, and Py/Py to correspond to the DNA base pair in the minor groove to be bound;
- L represents an amino acid linking group selected from the group consisting of β-alanine and 5-aminovaleric acid (δ);
- P represents a polyamide selected from the group consisting of X1X2X3γX4X5X6, X1X2X3X4γX5X6X7X8, X1X2X3X4X5γX6X7X8X9X10, and X1X2X3X4X5X6γX7X8X9X10X11X12, where X1-X12 are independently selected from the group consisting of β-alanine, pyrrole, hydroxypyrrole and imidazole;
- and
- A represents a positive patch consisting of a rigid group adjacent to a positively charged group.
3 more elements
A tandem-linked polyamide having the formula:
- wherein γ is —NH—CH2—CH2—CH2—CONH— hairpin linkage derived from γ-aminobutyric acid or a chiral hairpin linkage derived from 2,4-diaminobutyric acid;
- X1/X10, X2/X9, X3/X8, X4/X7, X5/X6, X′1/X′10, X′2/X′9, X′3/X′8, X′4/X′7, and X′5/X′6 represent carboxamide binding pairs which bind DNA base pairs and are selected from the group consisting of Hp/Py, Py/Hp, Py/Im, Im/Py, and Py/Py to correspond to the DNA base pair in the minor groove to be bound;
- L represents an amino acid linking group selected from the group consisting of β-alanine and 5-aminovaleric acid (δ);
- P represents a polyamide selected from the group consisting of X1X2X3γX4X5X6, X1X2X3X4γX5X6X7X8, X1X2X3X4X5γX6X7X8X9X10, and X1X2X3X4X5X6γX7X8X9X10X11X12, where X1-X12 are independently selected from the group consisting of β-alanine, pyrrole, hydroxypyrrole and imidazole;
- and
- A represents a positive patch consisting of a rigid group adjacent to a positively charged group.
3 more elements
A tandem-linked polyamide having the formula:
- wherein γ is —NH—CH2—CH2—CH2—CONH— hairpin linkage derived from γ-aminobutyric acid or a chiral hairpin linkage derived from 2,4-diaminobutyric acid;
- X1/X12, X2/X11, X3/X10, X4/X9, X5/X8, X6/X7, X′1/X′12, X′2/X′11, X′3/X′10, X′4/X′9, X′5/X′8, and X′6/X′7 represent carboxamide binding pairs which bind DNA base pairs and are selected from the group consisting of Hp/Py, Py/Hp, Py/Im, Im/Py, and Py/Py to correspond to the DNA base pair in the minor groove to be bound;
- L represents an amino acid linking group selected from the group consisting of β-alanine and 5-aminovaleric acid (δ);
- P represents a polyamide selected from the group consisting of X1X2X3γX4X5X6, X1X2X3X4γX5X6X7X8, X1X2X3X4X5γX6X7X8X9X10, and X1X2X3X4X5X6γX7X8X9X10X11X12, where X1-X12 are independently selected from the group consisting of β-alanine, pyrrole, hydroxypyrrole and imidazole;
- and
- A represents a positive patch consisting of a rigid group adjacent to a positively charged group.
3 more elements
Dependencies are inferred from the claim text.