Periodic Reporting for period 4 - EPiR (The Chemical Basis of RNA Epigenetics)
Berichtszeitraum: 2022-04-01 bis 2023-11-30
We indeed achieved development of a new prebiotic route to pyrimidine and purine nucleosides, based on simple molecules like formic acid, urea, hydroxylurea, sodium nitrite and isocyanate. This allowed us to generate purine and pyrimidine bases under prebiotically plausible conditions. We could show that this chemistry generates not only the canonical uridine bases A, G, C and U but also a large number of modified nucleobases (Nat. Comm. 2019), which are those that are indeed found today in contemporary RNA. We could therefore formulate the theory that the modified RNA bases that are today found in human RNA are indeed likely relics of an early earth chemistry and that they must have been present as competitor and companion molecules of the canonical bases. The corresponding publication in Science 2019 has received tremendous interest in the international press. The article was highlighted not only in a large number of scientific journals but also in the daily news. This publication formed next the basis to investigate the chemical synthesis of these modified bases as phosphoramidites and subsequently to explore their incorporation into RNA. Publications in this direction appeared in Angew. Chem. as a premium journal in organic chemistry and short, very competitive results were published in Chem. Comm. A further highlight of our study was the synthesis of the highly modified non-canonical nucleosides galactosyl- and mannosyl queuosine, which are sugar modified nucleobases present in the anticodon loop of tRNA. Here we could show that the chemical structure of mannosyl queuosine reported in the literature is wrong. We are in the process of correcting the chemical structure by total synthesis and direct comparison of the synthetic material with material isolated from various organs of higher organisms.
After having incorporated the modified nucleosides into RNA we are planning to move further into biology in order to investigate their function in more detail. Our goal is to study how the modified bases are interconverted in a living cell. We want to understand the reader, writer and eraser proteins that are binding to modified bases in order to elucidate the biological effect. The synthetic methods that were developed in the course of the 1st part of project have moved us far beyond the state of the art. They will be finally the basis for the synthesis of novel cyclic dinucleotide building blocks such as cGAMP derivatives, which may put us into the position to open up a new chapter in immuno-oncology. Our new synthetic methods are hoped to enable the efficient synthesis of cGAMP prodrug derivatives, which can enter cells to either stimulate or reduce the cellular immune-response against pathogens and cancer. A main result of our prebiotic and synthetic studies of modified bases may be the possibility to even synthesize immuno-stimulating cyclonucleotides that will help us to fight cancer.