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PROTAC, Proteolysis-Targeting Chimeras, is an emerging drug class that is different from antibodies and traditional small molecule inhibitors. After rapid development in recent years, remarkable progress has been made in the field of PROTAC. At present, several projects have entered the clinical evaluation stage, which brings unprecedented opportunities to solve the resistance of traditional small molecules and non-druggable target proteins.

Similar to PROTAC, RIBOTAC (Ribonuclease-Targeting Chimera) is designed to target RNA degradation. It's a bifunctional molecule that contains an RNA-binding module, a ribonuclease (RNase) recruitment module, and a linker. Once bound to the target RNA, RIBOTAC will recruit RNase near the target RNA, thereby facilitating its degradation.

The development of RIBOTAC is based on small molecules that can selectively bind RNA, especially RNA that can form complex secondary and tertiary structures. The key innovation is the conversion of RNA-binding molecules into RNA-degrading molecules by ligation RNase recruitment molecules.

In October 2021, a study published in the journal Science Translational Medicine, Matthew Disney, and his team designed a RIBOTAC molecule that degrades disease-causing RNA in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RIBOTAC was found to successfully induce the degradation of pathogenic mRNA and reduce associated pathology in both patient-derived spinal neurons and ALS mouse models. The results have led researchers to believe RIBOTAC has the potential to revolutionize treatments for diseases like ALS.

ALS and FTD are both progressive neurodegenerative diseases that cause the motor and cognitive impairment. These diseases are usually sporadic and the most common associated mutation is a hexanucleotide repeat expansion (HRE) of an intron in chromosome 9 open reading frame 72 (C9orf72) and this subtype of the disease is known as c9ALS/FTD.

RNA containing HRE is translated into a protein with a different dipeptide repeat structure (usually poly(GP) or poly(GA)). Both HRE-containing RNA and its translated dipeptide repeat protein are thought to promote neuronal death. RNA and proteins of this type can form toxic aggregates, and RNA can block gene expression.

Based on these early findings, scientists think that eliminating HRE-containing RNA may open up new opportunities to treat ALS and FTD. Targeting such disease-causing RNAs may be more effective as opposed to targeting proteins.

HRE-containing RNAs have another property: these RNAs can form a specific 3D structure, and targeting this unique 3D structure (rather than the primary sequence) may reduce the off-target effects of targeting other non-pathogenic mRNAs that contain shorter HRE.

A variety of RNAs, including mRNAs, miRNAs, and long non-coding RNAs, are associated with diseases and are therefore potential drug targets. RIBOTAC, as a novel molecule with the potential to target different types of RNA, may have certain advantages over antisense oligonucleotides (ASO) and siRNAs that have been developed to degrade RNA, including:

• Better pharmacokinetic properties: As a small molecule, RIBOTAC may enter a wider range of tissues, while ASO and siRNA have problems such as poor cellular uptake, poor tissue-specific delivery (except liver and kidney), and poor endosomal escape.
• Lower dose: The catalytic properties of RIBOTAC is another major advantage. After RIBOTAC binds and induces degradation of one RNA, it can bind another RNA. In this way, low concentrations of RIBOTAC can be used to achieve the degradation of the target RNA.

However, RIBOTAC also faces challenges that are difficult to develop, the most difficult part of which is the development of small molecules that selectively bind to target RNA in cells. Compared with antisense oligonucleotides, the development of suitable RNA-binding ligands is much more difficult because the former can be simply programmed to bind to target RNA using complementary sequences. In addition, RIBOTAC has poor cellular uptake and low bioavailability due to its large molecular weight. Further iterations of RIBOTAC may involve the search for smaller RNase-binding ligands, and it is of interest that small molecule activators of RNase L have been reported in the literature.

Reference

1. Bush, J. A., et al., Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(G4C2) repeat expansion in vitro and in vivo ALS models, Science Translational Medicine, 2021, 13.