SYNTHETIC ANTISENSE OLIGODEOXYNUCLEOTIDES AS POTENTIAL-DRUGS AGAINST HEPATITIS-C

Antisense oligodeoxynucleotides (ODNS) can be used to specifically inh ibit hepatitis C viral gene expression. Due to its high degree of cons ervation and its important function as internal ribosomal entry site, the 5'-non-coding region of the hepatitis C virus has been the most ef fective target to inhibit translation so far. Inhibition of luciferase reporter gene expression of up to 96 +/- 2% has been achieved. Modifi cations of ODNs like phosphorothioate, methylphosphonate or benzylphos phonate modification of terminal or intramolecular internucleotide pho sphates lead to altered lipophilicity and binding stability to its RNA target and resistance against serum nucleases, The mode of action of ODNs is mainly dependent on an efficient induction of RNase II activit y. The uptake of ODNs occurs via receptor-mediated or absorptive and f luid-phase endocytosis. After release from the endosomes, ODNs may exe rt their effects by interaction with cytosolic or nuclear structures. Side effects can occur when this interaction affects intra- or extrace llular targets essential for biological cell function. If these proble ms can be solved, antisense technology has the potential for future th erapy of human disease.