mRNA Regulation
In the last decade, the regulation of mRNA has become an emerging scientific discipline. Using our MOAi technology, we have exposed novel mRNA biology targets, allowing us to heavily contribute to advances in this space and become leading experts in mRNA biology.
The target space we explore encompasses proteins with specific biological roles in coordinating and regulating individual mRNA fate, and the pathways that regulate it. This allows for the discovery of small molecules that selectively modulate the mRNA fate of almost any protein of interest.
Our extensive mRNA biology knowledge and actual experimental outcomes are integrated into our Large Language Model (LLM), which is a component of our MOAi technologies. This LLM constantly works in sync with the platform components, refining our methodologies throughout each discovery project. It's like a continually updated asset in our system, making every research step smarter.
After identifying a disease's mRNA biology signature pathway, our MOAi technologies come into play to discover and validate novel targets. Compounds from our high-content screening emerge with pre-existing MOA rationale. Leveraging our vast proprietary data, the mRNA biology LLM suggests MOAs, which are then further confirmed by the co-pilot's experimental designs.
Visualizing mRNA regulatory mechanisms with Anima's mRNA Lightning imaging technologies
Our small molecules are targeting novel proteins involved in the regulation of mRNA
Various mechanisms enable cells to quickly respond to extracellular signals. The regulation around mRNA is extensive and those mechanisms provide novel intervention points for the development of novel therapies:
- Coordinated changes in translation initiation such as changing the components of the initiation complex
- Shuttling of mRNA, in a protected manner, to different cellular compartments where their translation is needed
- The use of non-protein vehicles to regulate mRNA stability, such as short-lived small noncoding RNAs (termed microRNA)
In different tissues, cells need to respond to distinct sets of cues. For example, mRNA translation in neurons is localized to different cellular compartments. Ribosomes are located around the nucleus, along exons, and at nerve endings to enable supply on demand of specific proteins required at these different cellular locations. Thus, to enable these diverse requirements and responses, mRNA translation has developed selective regulatory systems.
Biology
mRNA translation is a highly regulated process: once mRNA is transcribed, it is bound by RNA binding proteins (RBPs) in a highly specific and selective manner; an additional layer of regulation is mediated by modifications of ribonucleotides in mRNA (epitranscriptomics), that modulate RBP-mRNA interactions. Together these mechanisms regulate mRNA processing, nuclear export, and mRNA steady-state levels. RBPs regulate the localization of mRNAs in the nucleus and cytoplasm, thereby determining mRNA translation temporally and spatially. Moreover, ribosomes, much like RNA polymerases and proteasomes, have accessory proteins associated with them in a tissue and signal-specific manner, which provides mRNA translation an additional layer of selectivity.
Bi-directional mRNA translation regulation
Targeting the regulatory mechanisms of mRNA enables the discovery of compounds that not only decrease but can also selectively increase protein translation.
The images below are taken from Anima's Collagen I program. During the screening campaign, COL1A1 mRNA regulation inhibitors and activators were identified.
A compound that reduces the rate of translation of Collagen I decreases the light. Subsequently, this compound reduces Collagen I protein accumulation (middle panel).
A compound that enhances the rate of translation of Collagen I increases the light. The compound also enhances the production of Collagen I protein (right panel).