Design and Synthesis of Mechanism-Based Ribonuclease Inhibitors

• Applicant: Dr. Bjarne Silkenath
• Subject Area: Biological and Biomimetic Chemistry ; Biochemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: Funded in 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558477254

RNA-based therapeutics have gained significant importance not only since the COVID vaccines, but they face a major problem: they have limited stability in human media, primarily due to RNases that degrade RNA through their enzymatic activity. Current approaches to address this issue involve "packaging" the RNA for protection, but this method is expensive, can lead to unwanted immune reactions, and limits the application of these promising therapeutics. In this proposal, I suggest a strategy for deactivating RNases using small inhibitors. Specifically, I propose the use of uridine alkynyl phosphates, which are recognized by RNases and undergo the same cleavage reaction that RNA would normally undergo. However, in the case of alkynyl phosphates, this reaction releases a highly reactive electrophile that can then react with the active site of the RNase, thereby inhibiting it. I propose various approaches for the synthesis of these novel substances. Once an initial generation of inhibitors is synthesized, they can be tested in RNase inhibition assays. Based on the data obtained and the established synthesis methods, a second generation of even more effective inhibitors can be developed. Additionally, for the design of the second generation inhibitors, a computer-based approach will be utilized to predict better activity in silico.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Ronald T. Raines