On August 31, 2020 Arrakis Therapeutics, a biopharmaceutical company pioneering the discovery of a new class of small molecule medicines that directly target RNA, reported the publication of data demonstrating the capabilities of its proprietary PEARL-seq technology for the systematic identification of binding sites in RNA molecules, as an advanced research method to facilitate the discovery of RNA-targeted small molecule (rSM) medicines (Press release, Arrakis Therapeutics, AUG 31, 2020, View Source [SID1234564193]). The research was published online in the American Chemical Society’s peer-reviewed journal, ACS Chemical Biology, in an article titled "PEARL-seq: A Photoaffinity Platform for the Analysis of Small Molecule-RNA Interactions." PEARL-seq, which stands for Photoaffinity Evaluation of RNA Ligation-sequencing, is one of the chemical biology components of Arrakis’ proprietary end-to-end platform for discovery of rSM medicines.

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"PEARL-seq represents our innovative approach to establish target engagement, identify binding sites on the RNA, and learn about selectivity across the transcriptome," said Jennifer C. Petter, Ph.D., Founder and Chief Scientific Officer of Arrakis. "As part of Arrakis’ mission to drug RNA, we are building and refining the tools needed to discover and design rSMs against important RNA targets involved in disease."

The published study describes the development of PEARL-seq, which utilizes photoaffinity labeling of RNA in combination with next-generation sequencing and a dedicated bioinformatic analysis pipeline. Overall, the published work demonstrates the ability of the PEARL-seq platform to identify ligand binding sites within a model aptamer RNA as well as to identify potential off-target binding interactions. These data, combined with conventional RNA structure probing methods, can be used to generate and refine two- and three-dimensional structures of RNA-small molecule complexes, thereby facilitating the rational design of rSM therapeutics.

Key findings of the study include:

PEARL-seq enabled the identification of ligand binding sites as well as selectivity across RNAs in a single experiment.
The research showed that photoaffinity labels could be tethered to rSMs without disrupting the binding interactions between the rSM and the RNA. Upon activation with UV light, the rSM irreversibly crosslinks to the RNA, enabling mapping of the interaction by sequencing analysis.
The research further integrated RNA binding site characterization with transcriptome-wide sequencing to assess small molecule selectivity across the transcriptome.
Beyond binding site identification for directing RNA-targeted medicines, the results were integrated with multiple chemical probing data streams to support better informed two- and three-dimensional RNA structural predictions.
The researchers demonstrated the use of a DNA-encoded library screen to identify a novel small-molecule ligand to an aptamer RNA and used PEARL-seq to confirm a shared binding site with the original ligand.
"In this publication, we demonstrate the power of PEARL-seq to drive the rational design of rSMs," said Herschel Mukherjee, a chemist at Arrakis and a co-author of the publication. "Consistent with our platform-based approach, we combined photoaffinity labeling of RNA with refined sequencing and bioinformatics pipelines to develop a highly sensitive method for studying small molecule-RNA interactions."

"It was exciting to be a part of this close collaboration among the biology, chemistry and computational teams at Arrakis, along with external partners," added Craig Blain, a senior scientist and co-author of the publication. "‘Thriving as a team is an important part of how we work at Arrakis and has helped us build the PEARL-seq platform, a critical part of our mission to drug RNA."

Arrakis’ Platform for Developing rSM Medicines

Arrakis has developed a proprietary drug discovery platform for the systematic discovery and design of RNA-targeted small molecules (rSMs), by identifying small molecules that bind to and modulate RNA to predictably impact disease-related biology. The comprehensive drug discovery toolkit integrates leading‐edge RNA bioinformatics and chemical biology tools, RNA‐specific chemical and biological assays, and RNA-directed medicinal chemistry. By leveraging the best existing tools with Arrakis’ exclusive technologies, 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.