Structural Traps as RNA Therapeutics

RNA is the molecule in the cell which can transfer the code of DNA to make proteins. Some viruses like HIV and flu use it as their genetic material instead of DNA. Unlike DNA, RNA can change its shape very significantly and this allows it to interact with many different proteins in the cell. If we were able to lock the RNA in one particular shape it would not be able to bind on to to some of the proteins it needs to fulfil all of its functions. We now have sophisticated computer programmes which can generate models of the structures that RNA goes through and these models can be tested by chemical experiments. Once we know the shape of the RNA we can choose, from a library of chemicals whose structure we know, which of them best fits into the RNA structure. This will hopefully prevent the RNA from changing shape again. Using this approach we think we may have a new way of finding drugs which stop viruses like HIV, hepatitis and flu from multiplying. If the work is successful this might also be useful for other infections like meningitis and TB and might eventually even have applications in cancer treatment.

The aim is to study the molecular structure of important viral RNA motifs, initially from HIV-1, which have to undergo conformational change during their interactions with viral and cellular proteins. Using molecular modelling techniques, validated by experimental studies using FRET and NMR, we will model the structure of stable RNA intermediates between known (usually protein bound and non protein bound) conformers. We will use their charge and hydrophobicity/hydrophilicity landscape to select novel non nucleoside based small molecules from libraries of nucleic acid binding compounds which best fit the structure and can dock on to it and inhibit further conformational change. The effectiveness of this structural trapping will be validated by assessing the effect of these same RNA binding molecules in HIV replication assays. The work will progress to include other viral and non viral targets.