Description

A nucleic acids technology has evolved utilizing the specific recognition of nucleic acid sequences by biological nucleic acids and proteins. Efforts concentrate on gene silencing and other potential pharmaceutical applications. Long studied are “antisense” oligonucleotides. The idea is simple: Synthetic nucleic acid fragments are to bind stably and selectively to the mRNA of a pathogenic protein to block its expression. Unfortunately, in spite of an enormous input of money and labour, few oligonucleotide pharmaceuticals are on the market, of which only one is truly based on the antisense principle. The reason is, that these developments have met with a number of serious problems: 1. Extraneous nucleic acids are usually rapidly degraded in cells and body fluids. Therefore, antisense oligonucleotides have to be structurally modified in order to avoid breakdown. 2. A pathogenic protein can only be effectively eliminated, if the respective mRNA is irreversibly degraded. Ribonuclease H, for instance, cleaves DNA-RNA hybrid double strands, but often not recognizes complexes of mRNA with structurally modified oligonucleotides. 3. The efficient and targeted cellular uptake of antisense oligonucleotides is still a problem.;;This report focuses on two developments from our research: (1.) Methods have been developed to promote the internalization of oligonucleotides (a) by conjugation with “cell penetrating peptides”, (b) by the application of oligonucleotide-loaded nanoparticles. (2.) Since for the solid-phase production of oligonucleotide drugs the polymeric carrier is a major cost factor, supports with unusually high loading capacity have been developed. Such carriers can contain 400 µmol nucleotides per gram, still maintaining ca. 99% yield of stepwise chain elongation.;;Talk introduced by Mostafa Zedan.