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Opportunity

Application

Peptide-based inhibitors have been previously utilized to specifically target and inhibit certainly enzyme families, such as the Protein Arginine Methyl Transferases (PRMTs). The specificity of these inhibitors is conferred by the amino acids sequence, however the peptide backbone is highly susceptible to rapid degradation through proteolysis, which limits their overall efficacy in vivo. To mitigate the effects of hydrolysis, while still maintaining the specificity afforded by the amino acid sequences, faculty at the ¾ÅÉ«ÊÓƵ have developed peptoid-based compounds that inhibit PRMT enzyme activity with comparable specificity. Because the peptoid backbone is comprised of tertiary amides, which are much more resistant to hydrolytic degradation, these inhibitors show greater promise for development into therapeutics against cancers and other PRMT-associated diseases. Additionally, unlike cytotoxic chemotherapies that induce apoptosis and/or necrosis, these novel peptoid-based inhibitors appear to induce autophagy, which suggest they are less toxic cytostatic agents.

In vitro testing of the peptoid-based inhibitors demonstrate that they have no significant impact on normal cell lines, but they reduce growth and viability in breast carcinoma and colon carcinoma cells.

Invention Details

Methylation of arginine residues occurs on a number of protein substrates, most notably the N-terminal tails of histones, and is catalyzed by a family of enzymes called the protein arginine methyltransferases (PRMTs). This modification can lead to transcriptional activation or repression of cancer-related genes. To date, a number of inhibitors, based on natural peptide substrates, have been developed for the PRMT family of enzymes. However, because peptides are easily degraded in vivo, the utility of these inhibitors as potential therapeutics is limited.

The use of peptoids, which are peptide mimetics where the amino acid side chain is attached to the nitrogen in the amide backbone instead of the α-carbon, may circumvent the problems associated with peptide degradation. Given the structural similarities, peptoid scaffolds may provide enhanced stability, while preserving the mechanism of action. The inventors have identified that peptoids based on natural peptide substrates are not catalyzed to the product by PRMT1, but instead are inhibitors of this enzyme. Reducing the length of the peptoid reduces inhibition and suggest the residues distal from the site of modification are important for binding. Furthermore, a positive charge on the N-terminus helps promote binding and improves inhibition. Selectivity among family members is likely possible based on inhibition being moderately selective for PRMT1 over PRMT5 and provides a scaffold used to develop pharmaceuticals against this class of enzymes.

Patent pending. Invented by Dr. Bryan Knuckley and Dr. Corey Causey, Department of Chemistry, and Dr. Fatima Rehman, Department of Biology.