RNA-Targeting Small Molecules

A man in a lab coat working on a machine.

Breaking new ground into uncharted territory: Many proteins involved in harmful disease processes cannot be targeted by drugs – they are “undruggable”. Targeting them at the level of RNA could be the entry point yet into an unexplored universe of new treatment options for patients.

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Small molecules (SMOLs) have long been in the focus of modern medicine. Over the last century, their advent revolutionized healthcare and improved the lives of patients all over the world. Most of today´s SMOLs exert their function by binding to proteins, thereby modulating their ability to catalyze biochemical reactions. However, a lot of proteins are difficult targets for SMOLs, since they do not possess defined binding sites that can be used for SMOL drug candidates and this is making them hard to drug or even “undruggable”. A new and promising approach to solve this challenge may become possible in the future. The development of new technologies has recently unlocked a new class of target molecules for the application of SMOLs: ribonucleic acid, or in short: RNA.


Taking aim at RNA

RNA’s role in the development of many human diseases is well established. As a central mediator of information transfer and gene regulation, it is an essential component in all biological systems, as it for example carries the instructions for protein synthesis. To date, RNA remains more or less untargeted in conventional SMOL discovery, due to the fact that for a long time, it was not considered a potential target for SMOLs. One reason for this was its convoluted structures that comprise of single-stranded molecules folded into intricate secondary and tertiary structures. This is why, people used to compare the structure of an RNA molecule with the random appearance of a cooked spaghetti.


This has changed: we now know that these structures are highly ordered and critical to how RNA works, and it is precisely these complicated secondary and tertiary structures that could make RNA a viable target for SMOLs today.

The process of targeting RNA with SMOLs appears quite similar to the more established targeting of proteins. By binding to pockets in these RNA structures, SMOLs can alter the way RNA functions. For example, SMOLs can modulate the function stability of messenger RNAs, leading to an increased or decreased production of a certain protein. They can influence RNA localization and alter translation patterns.


Unlocking a universe of new targets

Targeting RNA with SMOLs could enable us to indirectly target proteins that are currently “undruggable” by preventing their synthesis. This way, the activity of many disease-related proteins could potentially be therapeutically altered in the future. In addition, we are taking aim at non-coding RNA. Non-coding RNA denotes those types of RNA that have functions beyond protein coding and can influence disease by regulating cellular signal transduction pathways or the translation of other coding RNAs. It accounts for a vast portion of RNA encoded by the human genome, which means that targeting non-coding RNA could potentially lead to a wealth of new therapeutic approaches that are currently out of reach for today’s medicine. Addressing these different biological mechanisms RNA-targeting small molecules could access a universe of new targets and with that totally novel therapeutic approaches.


Leading the change

Developing and establishing a novel game-changing technology platform for identification of RNA-targeting SMOLs is a big task that requires experience, expertise and commitment. At Bayer, we are now bringing together a team of experts whose sole focus is on the challenge of creating and developing RNA-targeting SMOLs and researching their potential applications. On the basis of our next-generation cell biology technologies and our library of more than 4 million compounds, we are integrating our leading capabilities in SMOL identification and design, as well as preclinical and clinical development to create a comprehensive new technology platform targeting RNA. With this endeavor, we continue to strive for leadership to develop innovative SMOL treatments for patients suffering from conditions with high medical need.