The increased life span achieved in the most societies correlates with an increased probability of an individual to be diagnosed cancer. The aging of the society leads to an increase of cancer prevalence which concomitantly increases the number of cancer deaths. Despite the impressive improvements of cancer treatments, we do require new concepts for personalized therapies with little side effects.
In cancer, gene expression is deregulated due to amplification, mutation and translocation of genes. Next generation RNA sequencing provides us with the opportunity to identify the number and identity of the gene products aberrantly expressed in a patient. We propose a method that could take advantage of the personalized sequence data. The idea is to use the RNA molecules produced in cancer cells as instructors for the chemical synthesis of drug-like molecules that cure the disease. Accordingly, drug-like molecules would only be formed in those cells that express the disease-specific RNA molecules. Such a personalized molecular therapy would eliminate side effects caused by unwanted perturbation of healthy cells.
The idea to use cellular RNA molecules as triggers for drug synthesis requires chemical methods that couple recognition of the “cancer RNA” with a change of chemical reactivity. Reactive molecules must be able to “read” and “translate” the sequence of a RNA molecule into a drug-like output. We will develop mRNA-triggered reactions that i) proceed with turnover in template to cope with low mRNA copy numbers and ii) allow the single-step synthesis of highly active drug-like molecules to address deregulated protein targets inside cancer cells. To achieve this aim, we will advance chemical acyl transfer and alkylidene transfer as well as photocatalytic cleavage reactions. The reactions will form peptides, peptidomimetics or small molecules which will bind and inhibit those proteins that allow the cancer cell to survive. Since the products will able to target both RNA (by virtue of the “read” step) and deregulated proteins (by virtue pf the “translate” step) synergy between the nucleic acid and protein worlds will be harnessed.
Conclusion: Over the 5 years on this project, we developed four different chemical reaction systems to put the formation of cancer toxic peptides and small molecule drugs under the control of RNA. We succeeded in demonstrating that conjugates comprised of a nucleic acid component and a peptide/small molecule can have enhanced potencly compared to the components alone. While we succeeded in demonstrating cellular delivery of the molecules we did not succeed in verifying that endogeneous RNA can instruct the intracellular synthesis of drug-like compounds. However, the reaction systems are promising for applications in DNA-encoded libraries which are frequently applied in drug screening. Our work on TRIGGDRUG led to the serindipitous discovery of a new reaction paradigm for nucleic acid templated reaction. We introduced reactions that induce cleavage within the main chain of nucleic acid molecules. These truly catalytic reaction systems enable the design of signal amplifying detection chemistries that may compete with the enzymatic methods used for example for the detection of viral RNA.
