Role of computational and structural biology in the development of small-molecule modulators of the spliceosome. (3rd October 2022)

• Record Type: Journal Article
• Authors: Rozza, Riccardo; Janoš, Pavel; Spinello, Angelo; Magistrato, Alessandra
• Is Part Of: Expert opinion on drug discovery. Volume 17:Number 10(2022)
• Page Start: 1095
• Page End: 1109
• Publication Date: 2022-10-03
• Subjects: Spliceosome -- Pre-mRNA splicing -- drug discovery -- splicing modulators -- molecular dynamics -- docking -- in silico drug design -- U2AF -- SF3B1 -- Brr2; 615.1
• DOI: 10.1080/17460441.2022.2114452
• Languages: English
• ISSNs: 1746-0441

Abstract

ABSTRACT: Introduction: RNA splicing is a pivotal step of eukaryotic gene expression during which the introns are excised from the precursor (pre-)RNA and the exons are joined together to form mature RNA products (i.e a protein-coding mRNA or long non-coding (lnc)RNAs). The spliceosome, a complex ribonucleoprotein machine, performs pre-RNA splicing with extreme precision. Deregulated splicing is linked to cancer, genetic, and neurodegenerative diseases. Hence, the discovery of small-molecules targeting core spliceosome components represents an appealing therapeutic opportunity. Area Covered: Several atomic-level structures of the spliceosome and distinct splicing-modulators bound to its protein/RNA components have been solved. Here, we review recent advances in the discovery of small-molecule splicing-modulators, discuss opportunities and challenges for their therapeutic applicability, and showcase how structural data and/or all-atom simulations can illuminate key facets of their mechanism, thus contributing to future drug-discovery campaigns. Expert Opinion: This review highlights the potential of modulating pre-RNA splicing with small-molecules, and anticipates how the synergy of computer and wet-lab experiments will enrich our understanding of splicing regulation/deregulation mechanisms. This information will aid future structure-based drug-discovery efforts aimed to expand the currently limited portfolio of selective splicing-modulators.