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Novel drug discovery and molecular biological methods, via DNA, RNA and protein changes using structure-function transitions: Transitional structural chemogenomics, transitional structural chemoproteomics and novel multi-stranded nucleic acid microarray.

Gagna CE, Lambert WC

Department of Pathology and Laboratory Medicine, New Jersey Medical School, Newark, NJ 07103, USA; School of Health Professions, Behavioral and Life Sciences, Department of Life Sciences, New York Institute of Technology, New York College of Osteopathic Medicine, Building #2, Room #362, Old Westbury, NY 11568-8000, USA.

Nucleic acids and proteins are dynamic molecules that undergo structural changes which control gene expression. The authors have developed two novel techniques, viz., transitional structural chemogenomics and transitional structural chemoproteomics. Transitional structural chemogenomics is used to regulate gene expression, employing ultrasensitive small-molecule drugs targeted toward nucleic acids. Gene expression can be regulated by using chemicals to target transitional changes in the helical conformations of single-stranded (ss-) and double-stranded (ds-) DNA (e.g., B- to Z-DNA), and RNA (e.g., A- to Z-RNA). This method also targets alternative types of ds- and ss-DNA and RNA (e.g., cruciform DNA), and other multi-stranded nucleic acids (e.g., triplex-DNA). Our second technique, transitional structural chemoproteomics, targets a protein before, during or after post-translational modifications which alters its structure and function. Both a proteins' structured and unstructured regions are targeted. These two novel methods represent the next step in the evolution of chemical genomics and chemical proteomics. They allow for two approaches to regulate gene expression, viz., turning genes "on", "off" or variable control (e.g., dimmer switch). This article also discusses the confusion that exists between the term chemical genomics and other related subdisciplines, such as chemical proteomics. Additionally, we have developed a novel multi-stranded DNA, RNA and plasmid microarray which immobilizes intact nondenatured ds-DNA, alternative, and other multiple-stranded nucleic acids onto a substrate surface. This technique represents the next generation of nucleic acid microarrays, which will enhance the characterization of nucleic acids and the drug discovery process. These three novel techniques allow for a multifaceted approach that will greatly enhance the success of molecular biology, the "omics" and drug discovery. They represent the next era of gene expression tools.

Published 10 July 2006 in Med Hypotheses.
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