Molecular forceps from combinatorial libraries prevent the farnesylation of Ras by binding to its carboxyl terminus

Introduction: Ras is one of the major oncogenes, In order to function prope rly it has to undergo post-translational processing at its carboxyl terminu s. It has been shown that inhibitors of farnesyl transferase, the first enz yme in the processing chain, can suppress the transforming activity of onco genic Ras. Results: We have identified molecular forceps, branched peptidic molecules, from combinatorial libraries that bind to the carboxyl terminus of Ras and interfere with its farnesylation without inhibiting the farnesyl transfera se. The active molecules were selected by a screening against the carboxy-t erminal octapeptide of Ras. Conclusions: The implications of our findings are twofold. First, we demons trate that it is possible to prevent enzymatic transformations by blocking the enzyme's access to its substrate using a synthetic small molecule to ma sk the substrate. Second, we show that it is feasible to derive molecules f rom combinatorial libraries that bind a specific epitope on a protein by se lecting these molecules with the isolated peptide epitope.