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

Friday, April 13, 2018


Dr. W. David Wilson

Chemistry

Georgia State University

Hand 1144, 3:30 PMWilson

Abstract:  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 non-gene 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

 

Bio:  W. David Wilson is currently Regents Professor in the Department of Chemistry at Georgia State University. He obtained a B.S. degree in chemistry from the University of North Carolina and a Ph.D. in biophysical chemistry from Purdue University. He began work on peptide-DNA interactions as well as anticancer drug design with Dr. Edmond Gabbay at the University of Florida. His research has centered on biophysical studies of the structure and interactions of nucleic acids. His recent interests have included development of calorimetric and biosensor-surface plasmon resonance methods for analysis of nucleic acid interaction thermodynamics, cooperativity, specificity and kinetics. He has spent much of his career at Georgia State University in Atlanta where he has had a long-term collaboration with Professor David Boykin on nucleic acid targeted drugs. He has a number of patents with Dr. Boykin on therapeutic agents that act through nucleic acid complexes. He has received international senior scientist awards for sabbatical research on nucleic acid complexes with Professor Stephen Neidle at the Institute of Cancer Research, London (NATO Grant), with Dr. Christian Bailly at the Institute of Cancer Research, Lille (INSERM International Senior Scientist Award) and with Professor Nand Kishore at the Indian Institute of Technology-Bombay (Visiting Senior Faculty Support Award, IIT-Bombay).. Dr. Wilson is a member of the Molecular and Cellular Biophysics Study Section at the National Institutes of Health. He co-edited a book in on nucleic acid interactions, Small Molecule DNA and RNA Binders: From Synthesis to Nucleic Acid Complexes, with Martine Demeunynck and Christian Bailly. He is author of over 400 publications and serves on the scientific, advisory and/or editorial boards of several companies and journals.


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