Structural basis of a small molecule targeting RNA for a specific splicing correction

Campagne, Sébastien; Boigner, Sarah; Rüdisser, Simon; Moursy, Ahmed; Gillioz, Laurent; Knörlein, Anna; Hall, Jonathan; Ratni, Hasane; Cléry, Antoine; Allain, Frédéric H.‐T.

doi:10.1038/s41589-019-0384-5

Cited by 117 publications

(166 citation statements)

References 53 publications

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“…Risdiplam's MOA was defined using a derivative dubbed SMN-C5 and a duplex model of the 5 0 splice site/U1 snRNP complex (Table S1, ESI †). 103 The model consisted of 11 nt of the 5 0 splice site hybridized to 11 nt of the U1 snRNA. The three-dimensional structure of this model with and without SMN-C5 was defined by NMR spectroscopy, constrained by nuclear Overhauser effects (NOEs).…”

Section: Small Molecules Modulate Smn2 Splicingmentioning

confidence: 99%

Small molecule recognition of disease-relevant RNA structures

et al. 2020

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Section: Small Molecules Modulate Smn2 Splicingmentioning

confidence: 99%

Small molecule recognition of disease-relevant RNA structures

et al. 2020

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“…These small molecules showed good oral bioavailability, as well as improved motor function and longevity in SMA mouse models [96][97][98]. NMR structures indicated that SMN-C5 specifically stabilised a bulged adenine at the exon-intron junction in the helix formed by U1 snRNA and exon 7 5'ss; therefore, promoting U1 snRNP recognition and converting the weak 5'ss into a stronger one [99]. This introduces a new concept for gene-specific alternative splicing correction termed as 5 splice site bulge repair.…”

Section: Small Molecule Sma Drug Candidates Correcting Smn2 Splicingmentioning

confidence: 99%

“…This introduces a new concept for gene-specific alternative splicing correction termed as 5 splice site bulge repair. Moreover, SMN-C5 worked cooperatively with the splicing regulatory network, thus, displaying higher potency in cellular models than in vitro assays [99]. Additionally, previous evidence indicated that SMN-C class compounds bound to the ESE2 region on exon 7, through potential mechanisms relevant to SMN2 splicing activators, including hnRNP G, far upstream element-binding protein 1 (FUBP1), and KH-type splicing regulatory protein (KHSRP) [100,101].…”

Section: Small Molecule Sma Drug Candidates Correcting Smn2 Splicingmentioning

confidence: 99%

“…Additionally, previous evidence indicated that SMN-C class compounds bound to the ESE2 region on exon 7, through potential mechanisms relevant to SMN2 splicing activators, including hnRNP G, far upstream element-binding protein 1 (FUBP1), and KH-type splicing regulatory protein (KHSRP) [100,101]. However, ESE2 binding is not the dominant cause of splicing correction, and the action mode of these RBPs are not fully understood [99]. Compared to RG7800, risdiplam showed enhanced potency and improved safety in preclinical studies [93].…”

Section: Small Molecule Sma Drug Candidates Correcting Smn2 Splicingmentioning

confidence: 99%

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RNA-Targeted Therapies and High-Throughput Screening Methods

Zhu

Rooney

Michlewski

2020

IJMS

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RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic shift in the knowledge base, with RNA increasingly being recognised as an attractive target for precision medicine therapies. In this article, we are going to review current RNA-targeted therapies. Furthermore, we will scrutinise a range of drug discoveries targeting protein-RNA interactions. In particular, we will focus on the interplay between Lin28 and let-7, splicing regulatory proteins and survival motor neuron (SMN) pre-mRNA, as well as HuR, Musashi, proteins and their RNA targets. We will highlight the mechanisms RBPs utilise to modulate RNA metabolism and discuss current high-throughput screening strategies. This review provides evidence that we are entering a new era of RNA-targeted medicine.

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“…PDD has identified game-changing medicines with novel mechanisms, including medicines for spinal muscular atrophy (SMA), cystic fibrosis (CF), and hepatitis C. The molecular basis of SMA entails inappropriate exon splicing of SMN2 RNA. "Black Box" cellular assay screens by two research groups independently identified small molecules which correct SMN2 RNA splicing and increase levels of SMN2 protein [14][15][16][17] . One interesting point here is the Novartis and Roche SMA screens were conducted with simple cell-based reporter gene assays.…”

Section: Introductionmentioning

confidence: 99%

Recent advances in phenotypic drug discovery

Swinney¹,

Lee²

2020

F1000Res

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There is a great need for innovative new medicines to treat unmet medical needs. The discovery and development of innovative new medicines is extremely difficult, costly, and inefficient. In the last decade, phenotypic drug discovery (PDD) was reintroduced as a strategy to provide first-in-class medicines. PDD uses empirical, target-agnostic lead generation to identify pharmacologically active molecules and novel therapeutics which work through unprecedented drug mechanisms. The economic and scientific value of PDD is exemplified through game-changing medicines for hepatitis C virus, spinal muscular atrophy, and cystic fibrosis. In this short review, recent advances are noted for the implementation and de-risking of PDD (for compound library selection, biomarker development, mechanism identification, and safety studies) and the potential for artificial intelligence. A significant barrier in the decision to implement PDD is balancing the potential impact of a novel mechanism of drug action with an under-defined scientific path forward, with the desire to provide infrastructure and metrics to optimize return on investment, which a known mechanism provides. A means to address this knowledge gap in the future is to empower precompetitive research utilizing the empirical concepts of PDD to identify new mechanisms and pharmacologically active compounds.

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Structural basis of a small molecule targeting RNA for a specific splicing correction

Cited by 117 publications

References 53 publications

Small molecule recognition of disease-relevant RNA structures

Small molecule recognition of disease-relevant RNA structures

RNA-Targeted Therapies and High-Throughput Screening Methods

Recent advances in phenotypic drug discovery

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