Evaluation of electrophiles for the development of covalent RNA-binders

• Applicant: Dr. Patrick Zanon
• Subject Area: Biological and Biomimetic Chemistry ; Biochemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515396515

Most approved drugs bind reversibly to their biomolecular targets based on how complementary the two structures are, similar to a key fitting into a lock. So-called covalent ligands can undergo a chemical reaction upon binding, resulting in the formation of an additional strong chemical bond, which is the basis for the mechanism of many drugs like aspirin and penicillin. These, like the vast majority of drugs, target proteins to exert their biological effects. Over recent years, targeting RNA has emerged as a promising alternative, particularly for diseases for which conventional protein-targeting drugs have been unsuccessful. While the design of covalently acting ligands has become commonplace for proteins, virtually no such efforts have been reported for RNA. With the chemical structures of proteins and RNAs being fundamentally different from each other, no guidelines exist on how to harness chemical reactivity to improve RNA ligand binding. The proposed project will address this by evaluating the reactivity of a large variety of different reactive motifs towards RNAs on the level of the structures they fold into as well as their nucleotide building blocks. These results will provide the basis for the subsequent two aims, which take diametrical approaches to drug discovery, with one focusing on an RNA for which non-covalent ligands already exist and the other allowing the identification of new RNA targets and corresponding covalent binders to engage them.The repetition of a unit of six nucleotides is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and previous studies have identified non-covalent ligands that can address this target. By attaching motifs that are suitable to react and form a covalent bond with this RNA motif, new binders will be synthesized that are expected to show an enhanced potency and inhibition of disease-associated processes. While this will be an important case study, covalent bond formation also allows ligands to bind target sites that are hard to address with non-covalent interactions alone. Therefore, in the last part of the project, a panel of small reactive molecules will be designed to map binding sites throughout all RNAs in cancer cells. While these compounds are not expected to have a high selectivity due to their small size, the identified interactions can be used to develop more elaborate, drug-like molecules. This work, therefore, will provide a first foothold to engage novel RNA targets and further insights into how different reactive motifs can be used to differentiate between RNA structures.This translational study will implement methods ranging from organic chemistry to molecular biology and pioneer the use of covalent ligands to target RNA. In this way, the project will probe potential avenues for covalent RNA-binders and further our understanding of their utility in the development of an entirely new kind of drugs with additional applications for the study of RNA biology.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Matthew David Disney, Ph.D.