Nucleic-acid- and cell-based therapeutics - Pharmaceutical Biotechnology: Concepts and Aapplications - page 448

DNA
(Specific gene)

Transcription

Antisense
oligonucleotides

mRNA

Translation

Protein

Biological
effect

Figure 14.13 Overview of the concept of the antisense approach: the end goal is the prevention of expres-
sion of a particular gene product (invariably a protein) by either blocking the transcription or translation of
that gene

binding, in most cases, occurs via Watson-Crick-based nucleotide base pair complementarity.
Binding prevents expression of the gene product by preventing either the transcription or transla-
tion process (Figure 14.13).

14.7.1 Antisense oligonucleotides and their mode of action

The nucleotide sequence of an mRNA molecule contains the encoded blueprint that dictates the
amino acid sequence of a protein. Because of this, the mRNA sequence is said to make 'sense'.
(This mRNA, therefore, is complementary to an 'antisense' DNA strand, i.e. it is the antisense
strand of DNA in a given gene that serves as template for the mRNA synthesis.) As long as at
least part of the nucleotide sequences of any mRNA is known, it becomes potentially possible
to synthesize chemically an oligonucleotide, either a ribo- or deoxyribo-nucleotide, whose base
sequence is complementary to at least a section of the mRNA sequence. As long as such an
'antisense' oligonucleotide can enter the cell, the complementarity of sequences can promote
hybridization between the mRNA and the antisense oligonucleotide (Figure 14.14).
Successful binding, however, does not depend alone upon Watson-Crick base complemen-
tary. It is also infl uenced by higher-order secondary and tertiary structures adopted by the RNA.