Targeted Degradation of Structured RNAs via Ribonuclease-Targeting Chimeras (RiboTacs)

ABSTRACT

Introduction

RNA structural motifs can serve as recognition sites for proteins or regulatory elements. Notably, these specific RNA shapes are directly related to many diseases. Targeting specific RNA motifs using small molecules is an emerging domain of study within the area of drug discovery. Targeted degradation strategies are a relatively modern technology in drug discovery, offering important clinical and therapeutic outcomes. These approaches involve using small molecules to selectively degrade specific biomacromolecules associated with a disease. ”Ribonuclease-Targeting Chimeras” (RiboTaCs) represent a promising type of targeted degradation strategy due to their ability to selectively degrade structured RNA targets.

Areas covered

In this review, the authors present the evolution of RiboTaCs, their underlying mechanism, and their in-vitro validation. The authors summarize several disease-associated RNAs that have been previously targeted for degradation using the RiboTaC strategy and discuss how their degradation led to alleviating disease-associated phenotypes in-vitro and in-vivo.

Expert opinion

There are several future challenges that still need to be adressed for RiboTaC technology to fully realize its potential. Despite these challenges, the authors are optimistic about its prospects, which have the potential to fundamentally transform the treatment of a wide range of diseases.

KEYWORDS:

• RiboTaC
• RNA
• RNase L
• Targeted degradation
• Therapeutics

Article highlights

• RiboTaC has the potential to introduce a novel therapeutic approach that utilizes small molecules to cleave RNA structures associated with diseases.

• RiboTaC has the capability to specifically cleave RNA structures through the recruitment of a Ribonuclease.

• Several validation assays for RiboTaC have been developed to evaluate the binding and activation of RNase L.

• While RiboTaC shows promising potential, it will encounter challenges in transitioning from in-vitro and in-vivo studies to clinical trials.

• The development of new RiboTaC small molecule recruiters capable of activating other Ribonucleases is necessary to expand the technology’s opportunities.

• RiboTaC offers new avenues for therapeutic intervention in diseases and provides advantages over conventional ‘occupancy-based’ treatments.

Declaration of interest

R.I. Benhamou is a member of the scientific advisory board of ReviR Therapeutics and is serving as a member of the Israel Chemical Society, the American Chemical Society and the Israeli RNA Society. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Abbreviations

ALS	=	: Amyotrophic lateral sclerosis
ALIS	=	: Automatic Ligand Identification System
ASO	=	: Antisense oligonucleotide
AuTaCs	=	: Autophagy Targeting Chimeras
DM	=	: Myotonic dystrophy
FECD	=	: Fuchs endothelial corneal dystrophy
FOXO1	=	: Forkhead box protein O1
FRET	=	: Fluorescence Resonance Energy Transfer
FSE	=	: Frameshifting element
FTD	=	: Frontotemporal dementia
FXS	=	: Fragile X syndrome
LyTaCs	=	: Lysosome Targeting Chimeras
PD-L1	=	: Programmed death-ligand 1
Qsox1-a	=	: Quiescin sulfhydryl oxidase 1 isoform
ProTaCs	=	: Proteolysis Targeting Chimeras
RAN	=	: Repeat-associated non-AUG
ReFRAME	=	: Repurposing, Focused Rescue, and Accelerated Medchem
RiboTaCs	=	: Ribonuclease Targeting Chimeras
RNase L	=	: Ribonuclease L
SDS PAGE	=	: Sodium dodecyl-sulfate polyacrylamide gel electrophoresis
TNBC	=	: Triple negative breast cancer
UTR	=	: Untranslated region

Additional information

Funding

The authors are funded by the Israel Cancer Research Fund, the Israeli Centers for Research Excellence from the Council for Higher Education, and the Israel Science Foundation via grant 1925/22.