Control of molecular shape for the recognition of nucleic acid secondary structures

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Guanine quadruplexes (G4s) are shapes of DNA and RNA which regulate critical events such as cell aging and death, and the production of proteins, in particular those responsible for the development and progression of cancers, infections and neurological disorders. We propose to create and study several families of agents capable of finding G4s in cells, signalling them by emitting light and/or acting on G4s in a controlled manner. The long-term therapeutic goals are to (i) generate `smart' drugs which can selectively act in diseases such as cancer, neurological disorders, viral and parasite infections, with limited effects on healthy tissues, and (ii) create `army knife platforms' capable of integrating many functions in one agent. For instance, we want to let the agents find the G4s, signal where they are, and make a `permanent' knot on the DNA in order to prevent diseases from evolving, all in one go. Such multimodal action will greatly facilitate optimizing the agents' action, and offer more effective and targeted medicine. The proposed research also addresses the lack of tools to advance the fundamental progress of the G4 field, with novel emissive species that can be tuned to the need of individual laboratories around the globe. All in all, the proposed work will benefit Canada and beyond by providing clinicians with innovative and selective potential therapies, as well as researchers with performant tools to advance their own laboratory exploration. The approach that is taken in this proposal by targeting G4s in DNA and RNA is important because many current drugs focus on inhibiting proteins, and therefore often lead to the emergence of resistance (through a slight change in protein composition), rendering drugs ineffective. Pharmaceuticals acting on nucleic acid structures, however, are much more difficult to counteract, and therefore such therapeutic agents are more likely to remain active. Similarly, traditional laboratory tools for G4 investigation have reached their limits as the field has progressed, and novel tools with higher performance and multiple functions are now needed. Developing the proposed new agents and tools will expose the highly qualified personnel (HQP) to a range of concepts, fields and techniques. They become proficient in handling complex data search engines, strategizing organic and coordination chemical syntheses. Mastering analytical tools for drug development and biological assays, and developing trouble-shooting skills and flexibility in achieving their scientific goals, give them a strong advantage in the pharma job market and beyond. In addition, the diverse nature of the work in this research program primes our HQP to communicate with a variety of audiences, thanks to a wide range of scientific collaborations, and opportunities for interactions with the general public and individual patients.