Screening Approaches for Targeting Ribonucleoprotein Complexes: A New Dimension for Drug Discovery

Abstract

RNA-binding proteins (RBPs) are pleiotropic factors that control the processing and functional compartmentalization of transcripts by binding primarily to mRNA untranslated regions (UTRs). The competitive and/or cooperative interplay between RBPs and an array of coding and noncoding RNAs (ncRNAs) determines the posttranscriptional control of gene expression, influencing protein production. Recently, a variety of well-recognized and noncanonical RBP domains have been revealed by modern system-wide analyses, underlying an evolving classification of ribonucleoproteins (RNPs) and their importance in governing physiological RNA metabolism. The possibility of targeting selected RNA–protein interactions with small molecules is now expanding the concept of protein “druggability,” with new implications for medicinal chemistry and for a deeper characterization of the mechanism of action of bioactive compounds. Here, taking SF3B1, HuR, LIN28, and Musashi proteins as paradigmatic case studies, we review the strategies applied for targeting RBPs, with emphasis on the technological advancements to study protein–RNA interactions and on the requirements of appropriate validation strategies to parallel high-throughput screening (HTS) efforts.

RNA packaging into extracellular vesicles: An orchestra of RNA‐binding proteins?

“…Among the inhibitors of LIN28 recently reviewed (D'agostino et al., 2019), a recent study investigated more on C1632 (N‐Methyl‐N‐[3‐(3‐methyl[1,2,4]triazolo[4,3‐b]pyridazin‐6‐yl) phenyl]acetamide), a compound already known to block the interaction between LIN28 and let‐7 (Chen et al., 2019; Roos et al., 2016). In particular, the authors found that C1632 was able to downregulate the programmed death ligand‐1 (PD‐L1) and inhibit the tumour growth in vitro and in vivo, suggesting that C1632 and its derivatives could be employed as multifunctional antitumor drugs (Chen et al., 2019).…”

Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

“…Although historically compound screens paired with binding assays have been favoured to develop protein-nucleic acid inhibitors (as for LIN28 [131]), the above recent successes demonstrate that when structural information is known, computer-based drug discovery is a viable method to discover and develop drugs against RBPs. Notably, due to the dynamic and flexible nature of the RNA-protein complex, structure-based drug discovery methods utilising x-ray crystallography cannot be used in isolation and require solution-based binding analyses within the testing pipeline, such as molecular dynamics and machine learning methods to improve the drug design [153].…”

The Academic Pill: How Academia Contributes to Curing Diseases

“…The Centre for Integrative Biology High-Throughput Screening and Validation (CIBIO-HTS) facility has been operating since 2011 within the University of Trento, Italy. 14 CIBIO infrastructure includes nine state-of-the-art core facilities, all independent from the university’s research groups and run by qualified personnel. The CIBIO-HTS facility supports the development of screening programs and offers an interactive and open environment to researchers willing to apply chemical and functional biology or image-based cytometry to their research.…”

“…This illustrates that academia is a rich source for novel assays as basic research is transformed into screens, leading to unexplored therapeutic avenues. Lastly, Baillargeon et al, 11 Moraes et al, 12 Otvos et al, 13 D’Agostino et al, 14 Birchall et al, 15 and Brennecke et al 16 are reviews of the screening efforts of screening laboratories and their networks, covering a wide range of applications. These reviews showcase how expertise in different fields allows academic projects to progress toward the clinic.…”