Cross-Functional Informatics Solutions for RNA Drug Discovery

RNA therapeutics have significant potential. As highlighted in Frontiers in Bioengineering and Biotechnology, RNA therapeutics represent a rapidly expanding category of drugs that can accelerate clinical solutions, enable personalized medicine, and potentially make the term “undruggable” obsolete. However, the novel methodologies used to create these therapies present unique R&D challenges.

RNA Modifications Optimize Impact

RNA therapeutics can target areas beyond the reach of small molecule drugs by disrupting biological pathways involved in protein production, rather than simply blocking protein active sites. There are various types of RNA therapeutics, such as antisense oligonucleotides (ASO), small interfering RNA (siRNA), mRNA vaccines, and different conjugates. Despite their differences, these RNA types often require chemical modification or specialized delivery systems to address challenges related to efficacy, metabolism, and pharmacokinetics, such as poor cellular uptake, high nuclease degradation, and low binding affinity for complementary sequences.

Non-Natural Residues/Monomers

To address the limitations of unmodified (“naked”) RNA, researchers can modify RNA structures through chemical changes to backbones, ribose sugars, base analogs, and other structural modifications like nucleic acid bridging and chemical conjugation.

A common backbone modification, especially in ASO design, is the incorporation of phosphorothioate linkages, where a non-bridging oxygen atom in the internucleotide phosphate group is replaced with sulfur. This modification can enhance nuclease resistance and increase protein binding, improving the pharmacokinetic profile of a candidate. The introduction of sulfur creates a chiral center at each modified phosphorus atom, resulting in two possible stereoisomeric forms. Studies show that chirally-pure phosphorothioate ASOs can be synthesized, but stereochemistry significantly affects pharmacological properties. Therefore, it is crucial for researchers to accurately capture different stereo forms.

As this example demonstrates, scientific innovation in chemical modifications is extensive. Robustly capturing and registering structural-modification definitions, and tracking their use, is essential for R&D teams to properly define and protect their intellectual property (IP).

RNA Modifications Bring New R&D Challenges

RNA therapies exemplify the merging of biology and chemistry. For researchers, this means chemists and biologists must collaborate closely to design RNA-based entities. Software solutions for data capture, management, and analysis must be flexible enough to handle new, unique entity types that are represented as both chemical structures and biological sequences. Traditionally, biology and chemistry research teams have worked in silos with specialized tools, workflows, and data that do not easily integrate, creating significant hurdles that can slow progress and impede innovation.

Most scientific informatics products were designed to support either chemistry or biology, but not both. Consequently, cross-functional teams working on RNA therapies often face a choice: use two separate systems for chemistry and biology data, or select one system that only properly supports one domain.

Consequences of a Non-Cross-Functional RNA R&D Solution

The absence of a truly cross-functional informatics solution can lead to several challenges for teams working collaboratively on chemically-modified biologies like RNA therapies:

• ​Multiple sources of truth for the same therapeutic entity, due to separate chemistry and biology representations in different systems
• ​Inexact data, resulting from biological registration systems that fail to capture full details of complex chemical modifications, such as non-natural residues
• ​Slow processes and cumbersome collaboration that undermine scientific rigor
• ​Weakened IP protection, for example, when biological registration does not capture full details of entities

Dotmatics offers a unified cross-functional informatics solution that supports both chemists and biologists, accommodating their unique approaches even when collaborating on the same project.

Dotmatics Cross-Functional RNA Discovery Solution

Successfully developing RNA-based therapeutic candidates requires a complex interplay of chemistry and biology. Dotmatics has created a cross-functional RNA Discovery Solution to support the collaborative R&D needed for RNA drug discovery. Designed with both chemists and biologists in mind, this solution enables innovative RNA research programs.

The Dotmatics RNA Discovery Solution provides:

• ​A single platform for chemistry and biology: The platform understands both domains, allowing biologists and chemists to capture data in a common system, ensuring a complete single source of truth for candidate entities.
• ​Customizable scientific search and dashboards: Users can search or browse their data using biology, chemistry, or a combination of both, and view results in project dashboards tailored to their preferences, whether focused on biology, chemistry, or a combination including supplemental data like screening results or sequence alignments.
• ​Flexible ELN: The Dotmatics Electronic Lab Notebook (ELN) can be customized for both biology and chemistry workflows and user preferences. Users can record and register robust candidate profiles by tracking key information that becomes searchable, such as candidate ID, name, creator, molecular weight, extinction coefficient, target, sequence-level information (e.g., sugar/base, base sequence, RNA base analog, sugar pattern), structural information (e.g., HELM string, InChI key), associated conjugate chemicals or entities, batch and lineage information, inventory data, and experimental and screening results (e.g., IC-50 dose-response curves, ELISA assay results, off-target mapping, biomarker assessment).
• ​Chemically-modified entity registration: Dotmatics’s registration capabilities support full chemical representation of biological entities, enabling complete scientific representation and chemical-uniqueness checking and search using compound structure and InChI keys. Registration for oligonucleotides includes a record of monomers and chemicals as the smallest functional units. Dotmatics has collaborated with the Pistoia Alliance to standardize monomer definitions and define best practices.
• ​Cross-domain assay and analysis support: Dotmatics supports cross-functional workflows and offers a robust range of tools for both biology and chemistry experiments, assays, and analyses, aiding in lead selection and prioritization, activity assessment, and efficacy and safety profiling.

Contact Dotmatics to learn how their cross-functional solutions can support RNA therapeutics research.