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Molecular forceps from combinatorial libraries prevent the farnesylation of Ras by binding to its carboxyl terminus
1Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Introduction:
Ras is one of the major oncogenes. In order to function properly it has to undergo post-translational processing at its carboxyl terminus. It has been shown that inhibitors of farnesyl transferase, the first enzyme in the processing chain, can suppress the transforming activity of oncogenic 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 transferase. The active molecules were selected by a screening against the carboxy-terminal octapeptide of Ras.
Conclusions:
The implications of our findings are twofold. First, we demonstrate that it is possible to prevent enzymatic transformations by blocking the enzyme's access to its substrate using a synthetic small molecule to mask the substrate. Second, we show that it is feasible to derive molecules from combinatorial libraries that bind a specific epitope on a protein by selecting these molecules with the isolated peptide epitope.
Insights
Researchers discovered molecular forceps that block Ras oncogene processing without inhibiting farnesyl transferase. This novel approach targets Ras farnesylation by masking its substrate, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Ras is a key oncogene requiring post-translational processing for function.
- Inhibitors of farnesyl transferase can suppress oncogenic Ras activity.
Purpose of the Study:
- To identify novel molecules that interfere with Ras post-translational processing.
- To explore an alternative strategy to inhibit Ras oncogenic activity.
Main Methods:
- Screening combinatorial libraries against the Ras carboxy-terminal octapeptide.
- Identifying branched peptidic molecules (molecular forceps) that bind to Ras.
Main Results:
- Discovered molecular forceps that bind to the Ras carboxyl terminus.
- These molecules interfere with Ras farnesylation without inhibiting farnesyl transferase.
Conclusions:
- Demonstrated substrate masking as a method to prevent enzymatic transformations.
- Showed feasibility of deriving epitope-specific binders from combinatorial libraries.