Prenylation inhibitors in renal disease

Abstract

Members of the superfamily of Ras GTPase signalling proteins (monomeric G proteins) require post-translational carboxy-terminal prenylation to function. Prenylation is the covalent attachment of a hydrophobic prenyl group (either farnesyl or geranylgeranyl), which localises the GTPase to cell membranes. Ras proteins exert substantial control on cell proliferation and gene-transcription events, and prenylation inhibitors are now included in clinical trials for cancer. Many renal diseases are highly proliferative and are driven by a range of profibrotic cytokines. We hypothesise that inhibition of prenylation could be of substantial therapeutic benefit in such diseases, providing greater selectivity against abnormal cytokine-driven proliferation and fibrogenesis than current treatments available to nephrologists.