[Antisense constructs, therapeutics of the future?].
Two lines of research were followed to obtain an adequate antisense effect. Natural oligonucleotides can degrade their mRNA targets catalytically, but are prone to enzymatic instability. Therefore, we looked for the minimal molecular modification, which would yield nuclease stable constructs, which can be taken up sufficiently to exert a selective antiproliferative effect. Small aliphatic diols conjugated at the 3'-end yielded such constructs, enabling selective tumor growth inhibition in an experimental in vivo situation. Further studies with complexing agents which increase their stability as well as uptake are ongoing. Another strategy aimed at obtaining strongly binding analogs, which would allow mRNA translation inhibition by steric interference. Hexitol nucleic acids (HNA) by virtue of their high and selective affinity for RNA, are therefore a prime candidate. When targeting the translation initiation regions, and using a lipofection protocol, nice activities were obtained at inhibiting Plasmodium, ICAM-1 and Ha-ras mRNA expression. Therefore, uptake should not be a limiting factor for the development of HNA as antisense therapeutics.
Van Aerschot
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Laboratorium voor Medicinal Chemie, Rega Instituut, Katholieke Universiteit Leuven, Minderbroedersstraat 10-B 3000 Leuven.
D000818:Animals; D016375:Antisense Elements (Genetics) / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006801:Humans; D009696:Nucleic Acids / Q000037:antagonists & inhibitors*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000187:drug effects*; D013873:Thionucleotides / Q000235:genetics*
D016375:Antisense Elements (Genetics); D009696:Nucleic Acids; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D013873:Thionucleotides
Antisense constructen, therapeutica van de toekomst?