Abstract
This introduction charts the history of the development of the major chemical modifications that have influenced the development of nucleic acids therapeutics focusing in particular on antisense oligonucleotide analogues carrying modifications in the backbone and sugar. Brief mention is made of siRNA development and other applications that have by and large utilized the same modifications. We also point out the pitfalls of the use of nucleic acids as drugs, such as their unwanted interactions with pattern recognition receptors, which can be mitigated by chemical modification or used as immunotherapeutic agents.
Highlights
Introduction and History of theChemistry of Nucleic Acids TherapeuticsMichael J
3.3 Heterocyclic Base Analogues most important bicyclic derivative of LNA that has found considerable therapeutic utility is the methylated analogue known as “constrained Ethyl”, which is being employed in shorter gapmers [98] (Fig. 4g) and being evaluated in preclinical and clinical studies by Ionis Pharmaceuticals Inc
Based on the progress to date and the promise of the results, nucleic acid therapeutics are being recognized as the third major drug discovery and development approach in addition to small molecules and protein/antibody approaches
Summary
Oligonucleotides are short single-stranded sections of DNA or RNA that contain 20-deoxyribo-nucleosides or ribo-nucleosides, respectively, which are linked by 30–50 phosphodiester linkages (Fig. 1a). Antisense oligonucleotides are those that are complementary to a section of naturally occurring RNA, such as an mRNA or a viral RNA, to form Watson–Crick base pairs and to inhibit a biological function of that RNA. Many further chemistry developments since in the use of synthetic oligonucleotide analogues, as outlined below, as well as advances in molecular biology, such as in the newer fields of short. Approval of Fomivirsen, discontinuations of clinical development of over 20 PS-ODN antisense. Approval of Mipomersen, discontinuations of clinical development of over 30 gapmer antisense, with MOE or LNA
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