Targeting the IRES structure of mRNA for modulating gene translation

Abstract

The c-Myc oncoprotein is a critically important cancer driver across a wide range of tumour types. Recent studies demonstrated that the translation of the c-myc mRNA could work as a potential Achilles’ heel for cancer treatment. These studies suggest that c-myc is a promising, although challenging, target for cancer therapy.

The c-myc mRNA internal ribosomal entry site (IRES) was initially targeted. IRESs are found in mRNAs encoding a number of different oncoproteins and allow mRNA translation to initiate independently of the canonical 5’-CAP and have been proposed as therapeutic targets. Activity of the c-myc IRES is increased in malignant cells compared to the healthy cells, providing a potential window for cancer selective c-myc inhibition.

It was proposed to use the base-pairing capacity of nucleic acids for highly selective targeting of the c-myc mRNA, thereby avoiding potential confounding effects of broader translational inhibition obtained with eIF4A blockade. The hypothesis is that antisense oligonucleotides (ASOs), specific for parts of the c-myc IRES, will lead to inhibition of c-myc translation. Importantly, the c-myc IRES structure has been derivatised using footprinting. This mapping of the c-myc IRES sequence has revealed a minimal 50-base sequence that was responsible for the bulk of the IRES activity. Within this element, two 14-nt segments were responsible for ribosome recruitment. This mapping provides the basis for our rational design of targeting ASOs. The designed oligonucleotides (ODNs) will contain modifiers for increased nuclease resistance and increased RNA-DNA duplex formation (e.g. LNA, phosphorothioate). The combination of these modifications is introduced as a key for modulating gene translation as the target RNA must not be degraded. To introduce these target sequences into human cells a suitable AuNPs@PEG@ssDNA has to be designed.

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Identifiers

ORCID for Albert Ferriol Monjo: orcid.org/0000-0003-0754-4716

ORCID for Eugen Stulz: orcid.org/0000-0002-5302-2276

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