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Chapter 30. Sequence-defined Oligonucleotides as Potential Therapeutics

1991; Elsevier BV; Linguagem: Inglês

10.1016/s0065-7743(08)61217-8

1557-8437

Mark D. Matteucci, Norbert Bischofberger,

DNA and Nucleic Acid Chemistry

The sequence-specific modulation of gene expression within a cell using oligodeoxynucleotide (ODN) analogs is a significant approach to potential therapeutics called antisense RNA because of the intent to down-regulate the expression of a disease-causing protein by inhibiting the translation of its precursor messenger RNA (mRNA). This chapter discusses recent work on the inhibition of gene expression using ODNs by mRNA hybridization through Watson Crick base pairing and the inhibition by triple helix formation with duplex genomic DNA. The antisense RNA and duplex targeting triple helix approaches share common features not usually required of drugs in an absolute sense such as stability in serum and tissue, access to intracellular targets, and ability to attain significant concentration levels in the cytoplasm and nucleus. These stringent pharmacokinetic and pharmacodynamic requirements are discussed in the chapter in the context of the antisense approach. ODN-mediated modulation of gene expression shows therapeutic potential. Preliminary studies have demonstrated the titration of transcription factors from their genomic DNA by using double-stranded ODN sequences identical to the genomic sequences bound by these factors. The approach for using sequence-defined ODNs as potential therapeutics is through binding to proteins and to small molecules.