Inhibition of major groove DNA binding proteins by modified polyamides
First Claim
Patent Images
1. 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.
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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.
28 Citations
25 Claims
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1. A polyamide molecule that specifically binds to base pairs in the minor groove of a DNA molecule, said polyamide molecule comprising:
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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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 23, 24, 25)
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19. 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 X1X2X3γ
X4X5X6, X1X2X3X4γ
X5X6X7X8, X1X2X3X4X5γ
X6X7X8X9X10, and X1X2X3X4X5X6γ
X7X8X9X10X11X12, 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.
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20. 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 X1X2X3γ
X4X5X6, X1X2X3X4γ
X5X6X7X8, X1X2X3X4X5γ
X6X7X8X9X10, and X1X2X3X4X5X6γ
X7X8X9X10X11X12, 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.
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21. 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 X1X2X3γ
X4X5X6, X1X2X3X4γ
X5X6X7X8, X1X2X3X4X5γ
X6X7X8X9X10, and X1X2X3X4X5X6γ
X7X8X9X10X11X12, 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.
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22. 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 X1X2X3γ
X4X5X6, X1X2X3X4γ
X5X6X7X8, X1X2X3X4X5γ
X6X7X8X9X10, and X1X2X3X4X5X6γ
X7X8X9X10X11X12, 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.
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Specification