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Retro-1-Oligonucleotide Conjugates. Synthesis and Biological Evaluation
Jordi Agramunt1, Enrique Pedroso2, Silvia M Kreda3
1Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and IBUB, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain. jagramuntpi@ub.edu.
Molecules (Basel, Switzerland)
|February 10, 2019
Summary
Small molecule Retro-1 was linked to oligonucleotides to enhance their activity. The resulting Retro-1 oligonucleotide conjugates were active but showed minimal advantage over unconjugated oligonucleotides in splice switching assays.
Area of Science:
- Oligonucleotide chemistry and molecular biology.
- Drug delivery and nucleic acid therapeutics.
Background:
- Small molecule Retro-1 is known to enhance the efficacy of antisense and splice switching oligonucleotides.
- Covalent conjugation of Retro-1 to oligonucleotides is a potential strategy to improve therapeutic outcomes.
Purpose of the Study:
- To synthesize and evaluate Retro-1 oligonucleotide conjugates for enhanced biological activity.
- To assess the efficacy of different conjugation strategies, including phosphoramidite, thiol, and diene modifications.
Main Methods:
- Preparation of three Retro-1 derivatives functionalized with phosphoramidite, thiol, or 1,3-diene groups.
- Assembly of Retro-1-oligonucleotide conjugates via on-resin phosphoramidite coupling, solution-phase thiol-maleimide Michael addition, and Diels-Alder cycloaddition.
- Evaluation of conjugate activity using splice switching assays in the HeLa Luc705 reporter system.
Main Results:
- Successfully synthesized Retro-1-oligonucleotide conjugates using various chemical strategies.
- The resulting conjugates demonstrated splice switching activity.
- However, the conjugates provided only a marginal improvement in activity compared to unconjugated oligonucleotides.
Conclusions:
- Covalent linkage of Retro-1 to oligonucleotides is feasible through multiple chemical approaches.
- While active, Retro-1-oligonucleotide conjugates did not significantly outperform unconjugated oligonucleotides in the tested reporter system.
- Further optimization or alternative conjugation strategies may be needed to realize the full potential of Retro-1 in oligonucleotide therapeutics.
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