Novel Proteinases: Dipeptidyl Peptidases 8 and 9 (DPP8 and DPP9)
Two new enzymes (DPP8 and DPP9) cloned and sequenced with multiple applications, including, selectivity screening of DPP-IV inhibitors.
The serine proteinases represent a large family of enzymes in which each family member has distinct substrate specificity. Prolyl oligopeptidases are serine proteinases which are responsible for cleaving the prolyl bond C-terminal adjacent to an amino-terminal dipeptide sequence, Ala-Pro or Gly-Pro. Very few enzymes are capable of cleaving this prolyl bond.
This family of enzymes are likely to be involved in the pathology of diseases, including tumour growth and biology, type 2 diabetes, cirrhosis, autoimmunity, graft rejection and HIV infection.
Two well-known examples of prolyl oligopeptidases are dipeptidyl peptidase IV (DPP-IV) and fibroblast activation protein (FAP). In particular, DPP-IV is currently of high pharmaceutical interest, primarily due to its demonstrated involvement in the pathology of Type-2 diabetes.
Merck recently gained approval for the first drug targeting DPP-IV, Januvia, for Type-2 diabetes, introducing a new generation of therapeutics.
The University of Sydney and Ferring Pharmaceuticals are working together to licence their combined patent portfolio of DPP patents.
Two new members of the prolyl oligopeptidase family have been fully cloned and sequenced (DPP8 and DPP9). There is high sequence homology with DPPIV, indicating that these sequences are likely to have similar tertiary structures.
However, the DPP8 amino acid is distinctive from DPPIV, particularly in the regions controlling substrate specificity. There is evidence that DPP8 and DPP9 inhibitors may act as immunostimulants.
Inhibition of DPP 8/9 by an experimental oncology agent in monocytes has been shown to induce the release of IL-1 (a key molecule stimulating immune responses), thereby stimulating cytokine and chemokine production.
Members of the proplyl oligopeptidase family are particularly important in the counter-screening of specific drug candidates where other members of the DPP family of enzymes are implicated, notably inflammation, cancer, and type II diabetes. The most prominent of these are inhibitors against DPP-IV.
A paper by Thornberry and Weber of Merck (Current Topics in Medicinal Chemistry, 2007) discuss the potential of toxic side effects in compounds that inhibit DPP8 and/or DPP9.
They quote: “determining the selectivity of our inhibitors was a key element of our medicinal chemistry program, and thus counterscreens for these enzymes [QPP, DPP8, DPP9 and FAP ] were developed”
It is therefore highly recommended that DPP8 and DPP9 be included in the selectivity screening panel for DPP-IV inhibitors. A service for testing potential inhibitors on DPP8 and DPP9 has also been established.
Selectivity screening for DPP-IV inhibitors; A potential target for immunostimulation.
- Dr. Mark Gorrell
- Ferring Pharmaceuticals