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Creating Highly Specific Chemically Induced Protein Dimerization Systems by Stepwise Phage Selection of a Combinatorial Single-Domain Antibody Library

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Completion of a Programmable DNA-Binding Small Molecule Library.

Carey F Hsu¹, John W Phillips, John W Trauger

¹Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125.

|July 4, 2008

Summary

This summary is machine-generated.

Researchers developed 27 hairpin pyrrole-imidazole (Py-Im) polyamides for sequence-specific DNA binding. These programmable molecules target specific gene sequences, offering new tools for molecular control of transcription.

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Area of Science:

Chemical Biology
Molecular Biology
Organic Chemistry

Background:

Hairpin pyrrole-imidazole (Py-Im) polyamides are programmable oligomers.
These molecules bind DNA minor groove sequence-specifically.
They exhibit affinities comparable to natural DNA-binding proteins and are cell-permeable, entering cell nuclei to regulate gene expression.

Purpose of the Study:

To complete a library of 27 hairpin Py-Im polyamides.
To characterize their binding to 7-base-pair DNA sequences (5'-WWGNNNW-3').
To provide binding data for the chemical biology community for molecular control of transcription.

Main Methods:

Synthesis of a library of 27 hairpin Py-Im polyamides.
Determination of equilibrium association constants (K(a)) for DNA binding.
Analysis of sequence specificity and binding affinities.

Main Results:

A library of 27 hairpin Py-Im polyamides targeting 7-base-pair sequences was completed.
Binding affinities (K(a)) ranged from 1×10(8) M(-1) to 4×10(10) M(-1).
Good sequence specificity was observed for the polyamide library.

Conclusions:

The completed library offers a valuable resource for researchers.
These polyamides provide molecular control over gene transcription.
The data facilitates the development of novel gene-targeting therapies.