Nestler 9728062 Encoded combinatorial chemistry has created a new paradigm in the quest for synthetic low molecular weight receptors. Branched peptidic molecules that can bind peptides in a sequence-specific manner have been found in encoded combinatorial libraries. The potential of this system is used in this study to derive low molecular weight receptors that are capable of binding to and modulating RAS proteins, which play central roles in signal transduction, and single amino acid mutations render the wild-type protein a potent oncogene. Experiments are designed to elaborate a new strategy for blocking biochemical processing. Instead of inhibiting the enzyme responsible for a biochemical modification, the substrate is rendered inaccessible for the transforming enzyme by small synthetic receptor molecules that bind to the domains to be modified. More specifically, small molecules that bind to the carboxy-terminal domain of RAS are derived from encoded combinatorial libraries of branched peptidic receptors. Stepwise screenings are used to select for tightly binding and highly selective "molecular forceps" with ability to interfere with RAS processing through preventing the attack of the farnesyl transferase to the carboxy-terminus of RAS. The results of this study and the methodologies developed to achieve them, should lay the groundwork for the discovery of small molecular agents that can modulate signal transduction pathways and other cellular processes of physiological importance.
