PSEUDODIPEPTIDE INHIBITORS OF PROTEIN FARNESYLTRANSFERASE

A series of pseudodipeptide amides are described that inhibit Ras prot ein farnesyltransferase (PFTase). These inhibitors are truncated versi ons of the C-terminal tetrapeptide (CAAX motif) of Ras that serves as the signal sequence for PFTase-catalyzed protein farnesylation. In con trast to CAAX peptidomimetics previously reported, these inhibitors do not have a C-terminal carboxyl moiety, yet they inhibit farnesylation in vitro at <100 nM. Despite the absence of the X residue in the CAAX motif, which normally directs prenylation specificity, these pseudodi peptides are greater than 100-fold selective for PFTase over type 1 pr otein geranylgeranyltransferase.