Interaction with the DNA Minor Groove by Designed Minor Groove Compounds: From Molecular Recognition to Therapeutics

Dr. David Wilson, Georgia State University
RHPH 164
Date / Time: 
Thursday, September 14, 2017 - 4:00pm
Dr. Danzhou Yang

It is now well established that, although only about 5% of the human genome codes for protein, most of the DNA has some function, such as synthesis of specific, functional RNAs and/or control of gene expression. These functional sequences open immense possibilities in both biotechnology and therapeutics for the use of cell-permeable, small molecules that can bind mixed-base pair sequences of DNA for regulation of genomic functions. Small, synthetic molecules that selectively target biological DNA in cells and induce specific biological responses, such as changes in gene expression, are a central goal of biomolecular compound design and synthesis research as well as therapeutic development. Unfortunately, very few types of modules have been designed to recognize mixed DNA sequences and for progress in targeting specific genes, it is essential to have additional classes of compounds. Compounds that can be rationally designed from established modules and which can bind strongly to mixed base pair DNA sequences are especially attractive. Approaches for compounds that can target the DNA component of DNA-protein complexes, for example, would help remove a block to progress in this field and provide an important step forward. Extensive experience in design of anti-parasitic minor-groove agents for AT DNA recognition has provided proof of concept that selective recognition of the DNA minor groove with a set of modules, combined in different ways for different sequences, is possible. New modular compound designs, which allow recognition of both AT and G·C base pairs in targeted DNA sequences, have now been prepared. This type of design approach can be expanded to additional modules for recognition of a wide variety of important sequences and inhibition of target protein-DNA complexes.

Supported by NIH GM111749

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