Inhibition of survivin by 2'- O -methyl phosphorothioate-modified steric-blocking antisense oligonucleotides

Yalin Li; Suxiang Chen; Kamal Rahimizadeh; Zhen Zhang; Rakesh N Veedu

doi:10.1039/d4ra01925c

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Inhibition of survivin by 2'- O -methyl phosphorothioate-modified steric-blocking antisense oligonucleotides

Journal article

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Peer reviewed

Inhibition of survivin by 2'- O -methyl phosphorothioate-modified steric-blocking antisense oligonucleotides

Yalin Li, Suxiang Chen, Kamal Rahimizadeh, Zhen Zhang and Rakesh N Veedu

RSC advances, Vol.14(19), pp.13336-13341

2024

DOI: https://doi.org/10.1039/d4ra01925c

PMID: 38660533

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Abstract

Chemically modified antisense oligonucleotide (ASO) has been established as a successful therapeutic strategy for treating various human diseases. To date, ten ASO drugs, which are capable of either inducing mRNA degradation via RNase H recruitment (fomivirsen, mipomersen, inotersen, volanesorsen and tofersen) or splice modulation (eteplirsen, nusinersen, golodirsen, viltolarsen and casimersen), have been approved by the regulatory agencies for market entry. Nonetheless, none of these approved drugs are prescribed as cancer therapy. Towards this, we have developed steric-blocking ASOs targeting BIRC5 – a well-validated oncogene. Initial screening was performed by transfection of HepG2 cells with seven BIRC5 exon-2 targeting, uniformly 2′-OMe-PS modified ASOs at 400 nM respectively, leading to the identification of two best-performing candidates ASO-2 and ASO-7 in reducing the production of BIRC5 mRNA. Subsequent dose–response assay was conducted via transfection of HepG2 cells by different concentrations (400, 200, 100, 50, 25 nM) of ASO-2 and ASO-7 respectively, showing that both ASOs consistently and efficiently inhibited BIRC5 mRNA expression in a dose-dependent manner. Furthermore, western blot analysis confirmed that ASO-7 could significantly repress survivin production on protein level. Based on our preliminary results, we believe that ASO-7 could be a useful BIRC5 inhibitor for both research purpose and therapeutic development.

Details

Title: Inhibition of survivin by 2'- O -methyl phosphorothioate-modified steric-blocking antisense oligonucleotides
Authors/Creators: Yalin Li - Henan University of Economic and Law
Suxiang Chen - Precision Nucleic Acid Therapeutics, Perron Institute for Neurological and Translational Science Nedlands WA 6009 Australia
Kamal Rahimizadeh - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
Zhen Zhang - Henan University of Economic and Law
Rakesh N Veedu - Precision Nucleic Acid Therapeutics, Perron Institute for Neurological and Translational Science Nedlands WA 6009 Australia
Publication Details: RSC advances, Vol.14(19), pp.13336-13341
Publisher: The Royal Society of Chemistry
Identifiers: 991005659469907891
Copyright: © 2024 The Author(s).
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 2 Chemistry; 2.170 Nucleic Acids Chemistry; 2.170.988 Oligonucleotide Modifications
Web Of Science research areas: Chemistry, Multidisciplinary
ESI research areas: Chemistry