Direct Activation of Nucleobases with Small Molecules for the Conditional Control of Antisense Function.

Autor: Bardhan A; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States., Brown W; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States., Albright S; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States., Tsang M; Department of Cell Biology, Center for Integrative Organ Systems., University of Pittsburgh, Pittsburgh, PA 15260, United States., Davidson LA; Department of Bioengineering, Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, United States., Deiters A; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Apr 22; Vol. 63 (17), pp. e202318773. Date of Electronic Publication: 2024 Mar 15.
DOI: 10.1002/anie.202318773
Abstrakt: Conditionally controlled antisense oligonucleotides provide precise interrogation of gene function at different developmental stages in animal models. Only one example of small molecule-induced activation of antisense function exist. This has been restricted to cyclic caged morpholinos that, based on sequence, can have significant background activity in the absence of the trigger. Here, we provide a new approach using azido-caged nucleobases that are site-specifically introduced into antisense morpholinos. The caging group design is a simple azidomethylene (Azm) group that, despite its very small size, efficiently blocks Watson-Crick base pairing in a programmable fashion. Furthermore, it undergoes facile decaging via Staudinger reduction when exposed to a small molecule phosphine, generating the native antisense oligonucleotide under conditions compatible with biological environments. We demonstrated small molecule-induced gene knockdown in mammalian cells, zebrafish embryos, and frog embryos. We validated the general applicability of this approach by targeting three different genes.
(© 2024 Wiley‐VCH GmbH.)
Databáze: MEDLINE
Externí odkaz: