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Published on: October 7, 2016
Alpha-diaminobutyric acid-linked hairpin polyamides
Michelle E Farkas1, Sherry M Tsai, Peter B Dervan
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Bioorganic & Medicinal Chemistry
|September 18, 2007
Summary
New hairpin polyamides using alpha-diaminobutyric acid (alpha-DABA) show enhanced DNA alkylation specificity. These compounds lock into a hairpin conformation, improving targeted DNA binding for potential therapeutic applications.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- DNA Interactions
Background:
- Hairpin polyamides are conjugates with potential biological applications.
- Previous characterization of alpha-diaminobutyric acid (alpha-DABA) linked polyamides regarding energetics and sequence specificity is lacking.
- Polyamides linked by gamma-diaminobutyric acid (gamma-DABA) are the standard.
Purpose of the Study:
- To characterize the energetics and sequence specificity of pyrrole-imidazole hairpin polyamides linked by alpha-DABA.
- To compare alpha-DABA linked polyamides with standard gamma-DABA linked polyamides.
- To investigate the DNA binding conformation of alpha-DABA polyamides.
Main Methods:
- Synthesis of pyrrole-imidazole hairpin polyamides with alpha-DABA and gamma-DABA linkers.
- Affinity cleavage studies using polyamide-EDTA conjugates.
- Comparison of binding affinities and sequence specificities.
Main Results:
- Alpha-DABA hairpins exhibited decreased overall binding affinities compared to gamma-DABA polyamides.
- Alpha-DABA polyamide-chlorambucil conjugates demonstrated sequence-specific DNA alkylation with increased specificity.
- Affinity cleavage studies confirmed a preference for forward hairpin DNA binding conformation for alpha-DABA polyamides.
- An unsubstituted glycine-linked polyamide showed a preference for an extended binding mode.
Conclusions:
- Substitution on the turn unit, specifically with alpha-DABA, effectively locks the polyamide into a forward hairpin binding motif.
- Alpha-DABA polyamides represent a new class of sequence-specific DNA alkylators with potential for enhanced therapeutic targeting.
- The conformational locking mechanism enhances DNA binding specificity, offering advantages over extended binding modes.
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