With the advancement in 2D-NMR methodologies, the structural investigatiOn of biological macromolecules has become routine. In recent past, interaction of drug molecules with Oligonucleotides or polypeptides, DNA-protein interaction have revealed fine structural details that illustrate the substrate-receptor binding, drug recognition profile, and structural abnormalities of oligonucleotides, and underline their implications in the design of potent biodynamic agents. Individual structural studies on oligonucleotide sequences containing abasic sites have been published, but a detailed account decoding the contribution of flanking base pairs of an abasic site on the overall structure of a DNA has not been accomplished. It becomes essential to furnish such a study, which would decipher the role of flanking base pairs in a DNA containing a carcinogenic abasic site lesion. A complete 2D-NMR study generating structural parameters required for the structure refinement by molecular dynamics strategies would furnish such account, which will aid in designing more potent drugs in the treatment of cancers. A whole new approach has been developed recently by few research groups, by designing oligonucleotides covalently linked to a minor groove binding drug and estimating their hybridization capability with other DNA and RNA sequences. Such strongly binding DNA conjugates have a potential of antisense agents, which selectively bind to specific sequences, thus blocking their further replication/transcription in the management of cancer and AIDS. This approach is heralding a new horizon in handling the mutant DNA/RNA sequences, while dealing with nucleoproteins of AIDS virus or mutagenic cells. A DNA conjugate containing a CDPI3 moiety, and two isoteric guanine, ppG residues, has been designed and prepared by our collaborators at Epoch Pharmaceuticals, which will be evaluated by 2D-NMR methods for structural details. This study will help developing more potent antisense/antigene agents. A collaboration with Dr. Barry Schweitzer of Walt Disney Memorial Cancer Institute, Orlando, FL/Molecular Staging, Inc., New Haven, CT has been established, who will assist in various aspects of the proposal, specially in structure refinement protocols.
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