Figure 1

Well characterized drugs that inhibit prenylation can also be used to inhibit viruses. The biosynthetic pathway from acetyl CoA to squalene and then on through multiple other steps (not shown) to ubiquinone, cholesterol and dolichol is shown. Statins inhibit HMG-CoA reductase and thereby prevent the synthesis of mevalonate and subsequent downstream lipids; statins also inhibit the replication of HIV [17]. Farnesyl pyrophosphate and geranyl pyrophosphate are the substrates for farnesyltransferase and geranylgeranyltransferase I and II, respectively. These enzymes catalyze the prenylation of proteins (blue hexagons), with farnesyltransferase catalyzing the addition of the 15-carbon farnesyl prenyl lipids to the cysteine of the tetrapeptide CXXX (where X is one of a possible three amino acids at the carboxyl terminus of the protein) and geranylgeranyltransferase I and II catalyzing the addition of 20-carbon geranyl prenyl lipids to CXXX, CC or CXC motifs. Farnesyltransferase inhibitors (FTI) block the farnesylation of proteins such as Ras and also inhibit the replication of hepatitis delta virus (HDV) [18,19]. Similarly, geranylgeranyltransferase inhibitors (GGTI) block the geranylation of proteins such as Rho and also inhibit the replication of HIV [17]. The prenylation of Ras and Rho proteins promotes their association with membranes and is therefore necessary for the targeting of these proteins to the plasma membrane, where they function.