Abstract
Addition of small molecule Retro-1 has been described to enhance antisense and splice switching oligonucleotides. With the aim of assessing the effect of covalently linking Retro-1 to the biologically active oligonucleotide, three different derivatives of Retro-1 were prepared that incorporated a phosphoramidite group, a thiol or a 1,3-diene, respectively. Retro-1–oligonucleotide conjugates were assembled both on-resin (coupling of the phosphoramidite) and from reactions in solution (Michael-type thiol-maleimide reaction and Diels-Alder cycloaddition). Splice switching assays with the resulting conjugates showed that they were active but that they provided little advantage over the unconjugated oligonucleotide in the well-known HeLa Luc705 reporter system.
Highlights
Forty years after the therapeutic potential of synthetic oligonucleotides was first perceived [1], delivery is the one problem that remains not well solved [2,3]
A few years ago, Juliano and cols. described that the compound named Retro-1 enhanced the pharmaceutical potency of antisense and siRNA oligonucleotides [9]
Retro-1 is a member of a group of compounds able to reduce the action of bacterial toxins [10] by interfering with their intracellular trafficking
Summary
Forty years after the therapeutic potential of synthetic oligonucleotides was first perceived [1], delivery is the one problem that remains not well solved [2,3]. Retro-1, the first compound identified to ameliorate both antisense and siRNA oligonucleotides effect, was chosen for this evaluation. In this manuscript we wish to describe the preparation of three. Retro-1, the first compound identified to ameliorate both antisense and siRNA oligonucleotides effect, was chosen. Retro-1 derivatives, their conjugation reactions to a splice switching oligonucleotide, and the results of the biological evaluation. These studies indicate that the efficacy of covalently linking the two. Retro-1 derivatives, their reactions to a splice oligonucleotide, moieties is inferior to thatconjugation achieved by administering the switching two separate molecules. These studies indicate that the efficacy of covalently linking the two moieties is Results inferior to that achieved by administering the two separate molecules
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