Arrakis RNA-targeted Small-Molecule (rSM) Platform

Our proprietary platform for the systematic discovery and design of RNA-targeted small molecules (rSMs) integrates leading‐edge RNA bioinformatics and chemical biology tools, RNA‐specific chemical and biological assays, and conventional medicinal chemistry. By leveraging the best existing tools with built-in-house technologies—TRYST, MARS and PEARL-Seq—we can, for the first time on an industrial scale, identify small molecules that modulate RNA function and predictably impact important biology in disease processes.

Click to explore our platform for discovering and developing rSMs:

ABOUT
rSMs

TARGET ID [TRYST)

computational analysis
structural analysis
functional relevance

SCREENING

primary HTS
secondary HTS
virtual screening

CONFIRMATION

SPR, SEC-MS, MST
effect of ligands on RNA structure
in vitro translation
cellular assays

MECHANISM [PEARL-seq)

binding site determination
selectivity across transcriptome
target engagement in cells

ARRAKIS rSMs

About rSMs

RNA-targeted small molecules (rSMs) are synthetic small molecules that modulate the expression level of proteins by impacting processing, transport, stability, or translation of their encoding RNAs. By selectively binding to functionally important regions in the RNA, rSMs can increase or decrease the levels of the target protein to treat disease.

TARGET IDENTIFICATION: TRYST™

TRYST™ is a novel sequence-to-structure engine for identifying and prioritizing novel RNA targets. It is a high-throughput, comprehensive system of bioinformatics concepts and tools, assays, and chemical libraries. SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) techniques are used to verify the structures that emerge from TRYST. To enhance SHAPE analysis, we have developed SHAPEware™, a computational tool that we have made publicly available.

SCREENING

Following the identification and validation of functional and therapeutically compelling RNA targets, screening is undertaken to identify small-molecule ligands that bind to the RNA targets. We have optimized multiple screening platforms to interrogate RNA, testing high-value targets across all of those platforms.

CONFIRMATION

Confirmation is an essential step to establish that the initially observed RNA-ligand interaction is robust and has biological impact. We perform multiple, distinct biophysical tests, including surface plasmon resonance (SPR), size-exclusion chromatography-mass spectrometry (SEC-MS), and ligand-observed nuclear magnetic resonance (NMR). In addition, we have optimized a battery of high-throughput human cell-free and cell-based translation and protein expression assays.

Having established molecular interaction, it is essential to demonstrate that binding of that RNA sub-structure impacts the biological function of the RNA. For example, if the targeted substructure plays an important role in translation of the transcript, then hits are tested in cell-free translation, cellular assays of translational function, and protein expression.

  • SPR, SEC-MS, NMR
  • effect of ligands on RNA structuren
  • in vitro translation
  • cellular assays

MECHANISM: PEARL-seq™

PEARL-seq™ is a suite of chemical biology tools to elucidate an RNA ligand's molecular mechanism of action. PEARL-seq tools enable our scientists to interrogate the secondary and tertiary structures of folded RNAs—both outside and inside of cells—to assess ligand binding site, target engagement, and selectivity of a small molecule; and to develop structure-activity relationship. These data are critical to the selection of superior candidate drugs for development.

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