Abstract
In the search for novel therapeutics, antisense oligonucleotide (ASO) analogs have been a major focus of research for over 40 years. They use the antisense strategy, namely they have a nucleic acid base sequence that is complementary to a portion of a specific mRNA that is produced in the cell, or to a viral RNA, in order to selectively inhibit gene expression. Oligonucleotides need to be chemically modified to stabilize them against hydrolysis by endogenous nucleases. Until now several phosphorothioate (PS) oligonucleotide analogs have been approved by the FDA for human use. This article seeks to provide a history of this subject to date.
Highlights
The basic premise of the antisense approach to therapy is that since most human diseases are genetic in origin, it is necessary to use a genetic means to cure them
Antisense depends on the intervention of information-containing drugs in the form of synthetic oligonucleotides to disrupt the flow of information transfer from DNA to RNA to protein.[1]
There are a myriad variations on these themes, but their general conclusion is that the future is with RNA oligo analogs
Summary
The basic premise of the antisense approach to therapy is that since most human diseases are genetic in origin, it is necessary to use a genetic means to cure them. At first the yield of PS analog was low due to the inefficiency of the sulfurization reaction[23] compared to the usual oxidation reaction.[24,25] We were able to increase the yield using a different solvent.[26] The oligomers were tested in an HIV assay and the PS oligomers showed excellent inhibition against the rev gene, but none with the PM oligos or the PO oligo controls.[27] disturbingly we found inhibition by the control sequence PS compounds, as well as PS homo-oligomers This led to further research using a more appropriate assay system using chronically infected cells that gave a pure sequence-dependent antisense inhibition, with the same controls as before (Figure 3).[28]. After 24 hours a punctate distribution (i.e discrete points of fluorescence) was observed, and this was taken to mean that uptake occurred, but that it was by the formation of vesicles within the cells (non-vesicular up-take would give a homogeneous distribution) (Figure 5).[54]
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