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Molecular Aspects of Small Molecules-Poly(A) Interaction: An Approach to RNA Based Drug Design

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Abstract:

The use of small molecules to specifically control important cellular functions is an area of major current interest at the interface of chemical biology and medicinal chemistry. Recognition of ribonucleic acids (RNA) has emerged more recently as a critical event in many biological pathways of eukaryotic cells and consequently the opportunity of drugs targeting to diverse structures of RNA is abundant. Such RNA targeting molecules must be able to specifically bind to unique structural organizations in RNA to regulate the gene expression. One particular example in this context is the modulation of the mRNA through its polyadenylic acid [poly(A)] tail. All mRNAs in eukaryotic cells have a poly(A) tail at the 3'-end This tail of about 200-250 or so adenine residues is an important determinant in maturation, stability of poly(A) and in initiation of translation process. Small molecules that could bind to this poly(A) tail could influence and possibly inhibit mRNA function and subsequent protein production in the cell leading to the development of new type of therapeutic agents. Recent discovery of the over expression of neo polyadenylic polymerase, the enzyme that catalyses polyadenylation, in human cancer cells compared to normal cells further signifies the importance of poly(A) in cellular events in cancer progression. The structural transition in poly(A) from single strand to double strand form induced by a narrow pH, salt and temperature variations also makes it a potential target for the better understanding of structurefunction relationship in nucleic acids. Over the last forty years attempts have been made for the structural elucidation of this polyribonucleotide as well as the complex formed by the interactions with various small molecules like DNA intercalators, partial intercalators and groove binders using various physico-chemical and technique. These studies have led to progress in the understanding of specificity of binding, correlation between structural and thermodynamic aspects, description of drug-RNA binding modes and influence of substitutents on drug-RNA complexes and ultimately the discovery of new novel compounds that can be used as modulators of poly(A) structure. This review focuses on the structural and biological significance of poly(A), the use of small molecules to control the structure of this RNA and the futuristic development of new small molecules targeted to poly(A) structures.

Keywords: Polyadenylic acid; binding; calorimetry; dye; groove binders; intercalators; self-structure; small molecules; spectroscopy

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986709787581932

Affiliations: Biophysical Chemistry Laboratory, Indian Institute of Chemical Biology, Kolkata 700032, West Bengal, India.

Publication date: March 1, 2009

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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