Arrakis RNA 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 structural biology tools, RNA‐specific chemical and biological assays, and conventional medicinal chemistry. By leveraging the best existing tools with inhouse-built technologies—TRYST and PEARL-Seq—we can, for the first time on an industrial scale, identify small molecules that modulate RNA function.

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 chemically based 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.

TRYST™ Predicts Structures and Binding Pockets

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 confirm the structures that emerge from TRYST. To enhance SHAPE analysis, we have developed SHAPEware™, a computational tool that we have made publicly available.

SCREENING

The identification of functional and therapeutically compelling RNA structures enables screening against those structures to identify small-molecule ligands. We have optimized multiple screening platforms for a survey of RNA structures, often testing high-value targets across all of those platforms.

CONFIRMATION

Screening yields candidate ligands binding to RNA structures, but it is essential to confirm specific RNA/ligand interactions using multiple distinct biophysical techniques. These methods include surface plasmon resonance (SPR), size-exclusion chromatography-mass spectrometry (SEC-MS), and nuclear magnetic resonance (NMR).

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

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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