Reprogramming RNA processing: an emerging therapeutic landscape. (May 2022)

• Record Type: Journal Article
• Authors: Neil, Christopher R.; Seiler, Michael W.; Reynolds, Dominic J.; Smith, Jesse J.; Vaillancourt, Frédéric H.; Smith, Peter G.; Agrawal, Anant A.
• Is Part Of: Trends in pharmacological sciences. Volume 43:Number 5(2022)
• Page Start: 437
• Page End: 454
• Publication Date: 2022-05
• Subjects: molecular therapeutics -- RNA splicing -- 3′ end processing -- small molecule compounds -- antisense oligonucleotides -- gene regulation; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2022.02.011
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : The production of a mature mRNA requires coordination of multiple processing steps, which ultimately control its content, localization, and stability. These steps include some of the largest macromolecular machines in the cell, which were, until recently, considered undruggable due to their biological complexity. Building from an expanded understanding of the underlying mechanisms that drive these processes, a new wave of therapeutics is seeking to target RNA processing. With a focus on impacting gene regulation at the RNA level, such modalities offer potential for sequence-specific resolution in drug design. Here, we review our current understanding of RNA-processing events and their role in gene regulation, with a focus on the therapeutic opportunities that have emerged within this landscape. Highlights: mRNA is the result of tightly regulated RNA-processing mechanisms and has a key role in defining proteomic expression, diversity, and cellular fitness. Small-molecule and antisense oligonucleotide-based therapeutics have shown promise in influencing the RNA processing of selective targets, with US Food and Drug Administration-approved drugs for both modalities and new experimental agents in preclinical and clinical development. Targeting RNA processing provides the opportunity to use nucleic acid sequence specificity to approach targets that are challenging to drug at the protein level. Advances in RNA-based platforms and technologies in the space of next-generation sequencing, bioinformatics, structural biology, screening methodologies, and chemistry are converging to inform the rational design of novel therapeutics.