Diabetes drugs must be precisely targeted

When enzyme inhibiting drugs to treat diabetes were being developed, Mark Gorrell warned that care was needed to ensure the drugs targeted a specific enzyme, leaving other members of the enzyme family unaffected.

Thankfully, his warning was heeded by drug companies.

Associate Professor Mark Gorrell and his team of liver researchers at Sydney’s Centenary Institute have now confirmed that the diabetes drugs and potential cancer therapies based on regulating the dipeptidyl peptidase (DPP) family of enzymes must be carefully targeted to avoid serious side effects such as skin and intestinal damage.

GorrellIn doing so, the scientists may have turned up a potential cause of infant mortality.  The work was published last week in the online journal PLOS ONE.

The inhibition of enzyme DPP4 activity is the basis of a leading drug treatment for diabetes. DPP4 inhibitors are worth about $6 billion a year and comprise about a quarter of the diabetes drug market. All licensed DPP4 inhibitors are DPP4-specific.

Inhibiting the action of DPP9 is also under investigation as a cancer therapy in adult humans. But the researchers found that mice lacking an active form of the enzyme DPP9 die as newborns after developing quite normally to that point.

Dr Gorrell and his group were the first to discover and clone DPP9.

Finding out just how critical DPP9 is to the survival of newborn mice—and the fact that its activity cannot be compensated by any other enzyme —“was unexpected,” Dr Gorrell says.

“If removing DPP9 activity is as dangerous for humans at an early age as it clearly is for mice, then DPP4 inhibitors really do have to be DPP4-specific. It’s possible that DPP9 is essential in humans too, and that its lack may cause problems in early infancy. But we’re only just starting to look at that possibility.”

The Centenary researchers explored the impact of DPP9 activity by incorporating a gene into mice which produced an enzyme exactly the same as DPP9, except that it is inactive. The development of pups with the faulty enzyme was entirely normal through pregnancy and birth—even to the point of suckling—but they all died as newborns. At present, the cause of their death is unknown.

There has been a recent upsurge of interest in DPP9 inhibitors after evidence emerged that may be useful in cancer therapy. By dampening the activity of DPP9, some inhibitors are able to activate the immune system and slow down tumour growth, Dr Gorrell says.

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Background Information

Paper Abstract

Dipeptidyl Peptidase (DPP) 4 and related dipeptidyl peptidases are emerging recently as current and potential therapeutic targets. DPP9 is an intracellular protease that is regulated by redox status and by SUMO1. DPP9 can influence antigen processing, EGF-mediated signalling and tumour biology. We made a gene knock-in (gki) mouse with a serine to alanine point mutation at the DPP9 active site (S729A). Weaned heterozygote DPP9wt/S729A pups from 110 intercrosses were indistinguishable from wild-type littermates. No homozygote DPP9S729A/S729A weaned mice were detected. DPP9S729A/S729A homozygote embryos, which were morphologically indistinguishable from their wild-type littermate embryos at embryonic day (ED) 12.5 to ED 17.5, were born live but these neonates died within 8 to 24 hours of birth. All neonates suckled and contained milk spots and were of similar body weight. No gender differences were seen. No histological or DPP9 immunostaining pattern differences were seen between genotypes in embryos and neonates. Mouse embryonic fibroblasts (MEFs) from DPP9S729A/S729A ED13.5 embryos and neonate DPP9S729A/S729A mouse livers collected within 6 hours after birth had levels of DPP9 protein and DPP9-related proteases that were similar to wild-type but had less DPP9/DPP8-derived activity. These data confirmed the absence of DPP9 enzymatic activity due to the presence of the serine to alanine mutation and no compensation from related proteases. These findings suggest that DPP9 enzymatic activity is essential for early postnatal survival in mice.

Read the full paper: www.plosone.org/;jsessionid=B2FE2849CBECC52BF72268DBDE6CD3C2

About Mark Gorrell

Associate Professor – Centenary Institute of Cancer Medicine & Cell Biology

Group leader – Molecular Hepatology Group

Mark D. Gorrell is devoted to understanding the functions of the dipeptidyl peptidase IV [DPP4] gene family enzymes and the molecular basis of chronic liver disease and how to exploit this knowledge to alleviate human illness. DPP4 is the target of a successful new type 2 diabetes therapy that is benefiting millions of patients. Improving understanding will lead to improved therapy for chronic liver disease sufferers, whether their illness is hepatitis B or C, autoimmune disease or fatty liver disease. Authorship: 110 publications including 5 patents, with about half the publications involving the dipeptidyl peptidase 4 gene family and most of the remainder on liver disease pathogenesis. Mark trained at Australian National University [BSc, PhD], University of Melbourne School of Veterinary Science and Johns Hopkins University School of Comparative Medicine and Department of Neurology before joining Royal Prince Alfred Hospital then Centenary Institute and Sydney Medical School.

About the Molecular Hepatology Group

Molecular hepatology research is focused upon understanding the functions and functioning of enzymes of the dipeptidyl peptidase IV [DPPIV] gene family and harnessing that knowledge to improve human health, particularly liver diseases and disorders. In addition, we work with the Pharmacy Faculty at the University of Sydney on ways to better understand and use the liver/brain enzyme Kynurenine Aminotransferase 1 [KAT-1].

More at: www.centenary.org.au/p/ourresearch/liver/Liver_Injury_and_Can/DiabetesandMolecular

About the Centenary Institute

The Centenary Institute is an independent leader in medical research seeking improved treatments and cures for cancer, cardiovascular and infectious diseases. We are working to discover new prevention, early diagnosis and treatment options to enable each generation to live longer, healthier lives than the one before. Centenary’s affiliation with the RPA Hospital and the University of Sydney means that our discoveries can be quickly applied to the fight against disease in the clinic.

More at: www.centenary.org.au and www.centenarynews.org.au