Well-Characterized Enzymes Could Have Potential In Drug Discovery

A collaboration between the University of Cambridge in the UK and AstraZeneca’s R&D unit, MedImmune, has discovered that well-characterized enzymes may have the potential to treat certain diseases, and further the drug discovery process. The results of the research were published in the journal, Chemistry and Biology.

Enzymes catalyze many diverse reactions inside cells, and their functions have often been well-characterized. The researchers point to the enzyme MMP8, which functions by breaking down collagen in the body, but could also be useful in the treatment of respiratory diseases such as asthma.

As the costs associated with developing and synthesizing novel enzymes continues to rise, developers are increasingly looking to repurpose enzymes native to biological systems, to uncover their treatment potential for certain diseases. The researchers at the University of Cambridge in association with MedImmune, identified 27 known human enzymes and proteases – enzymes that break the bonds between amino acids that form proteins – and used technology developed by MedImmune to test them against 24 protein drug targets.

Interestingly, the study investigators found 23 previously-unidentified enzyme activities. They identified a particularly fascinating new activity of the collagen-catalyzing enzyme, MMP8.

The researchers studied the enzyme’s activity further by using cell cultures genetically-engineered mice, and found that MMP8 had the ability to block the action of IL-13 – a molecule that has been implicated in dermatitis, asthma and a host of other inflammatory conditions. They postulate that MMP8 could regulate IL-13, which explains why the majority of the population aren’t afflicted with these inflammatory diseases.

If the interaction is confirmed to be the same in humans, the discovery could pave the way for new treatment options for patients suffering from these illnesses. “Because the enzyme already had a ‘name’ and a function, nobody thought to see if it had a promiscuous side,” said Dr. Florian Hollfelder, the principal investigator on the study from the University of Cambridge.

Hollfelder and his team say they have identified the promiscuous roles of additional well-characterized enzymes, which could have the potential to treat other diseases. If the predictive technology developed by MedImmune were to be applied to other enzymes, a multitude of new drugs could be discovered.

Sources:

• Known enzymes could be treasure trove for drug discovery – http://www.medicalnewstoday.com/articles/303268.php
• Urbach, C., Gordon, N., Strickland, I., Lowne, D., Joberty-Candotti, C., May, R., Herath, A., Hijnen, D., Thijs, J., Bruijnzeel-Koomen, C., et al. (2015). Combinatorial Screening Identifies Novel Promiscuous Matrix Metalloproteinase Activities that Lead to Inhibition of the Therapeutic Target IL-13. Chemistry and Biology, 22 (11), 1442-1452.