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Centenary Institute - Medical Research
Centenary Institute - Medical Research

COMMENT: DPP9 enzyme deficit could be key to severe COVID-19 infection

The first study of human gene associations with severe COVID-19 has just been accepted for publication in the highly prestigious journal ‘Nature’.

In the study, led by Dr Kenneth Baillie at the University of Edinburgh, five genetic sequences associated with severe COVID-19 illness were found. The sequences are known to be involved with inflammation and the body’s defence mechanisms.

Professor Mark Gorrell, Head of the Centenary Institute’s Liver Enzymes in Metabolism and Inflammation Program, comments, “I’m particularly interested in this study because one of the proteins identified by this large UK consortium as being associated with severe COVID is an enzyme that we discovered and which we are continuing to investigate at the Centenary Institute, called dipeptidyl peptidase 9 or DPP9.”

“DPP9, an enzyme encoded by the DPP9 gene, has many functions including several related to immune responses and cell growth and cell movement. Potentially most significant to COVID-19, in which inflammation can get out of control, is that DPP9 restrains inflammation. So, we think that possibly a deficit in DPP9 may be exacerbating inflammation.”

Professor Gorrell says that his ongoing work with DPP9 and this Nature paper show that few people have a deficit in DPP9.

“This may be one of the reasons as to why many people experience no symptoms from the illness, while a small minority of others become critically ill.”

Professor Gorrell and his group first discovered the enzyme DPP9 in 1999.  

Decreasing atherosclerosis risk

Co-operation between cardiovascular researchers from the University of Zurich with researchers from the ‘Liver Enzymes in Metabolism and Inflammation Program’ at the Centenary Institute have produced a breakthrough in understanding how atherosclerotic plaques (fatty deposits in arteries) form and stabilise.

The researchers showed that mice lacking an enzyme called FAP were healthier and developed lower rates of atherosclerosis. The researchers also discovered that the atherosclerotic plaques that did form in these mice were more stable and therefore less dangerous.

“Drugs that target FAP are being developed for cancer therapy, heart fibrosis, liver fibrosis, rheumatoid arthritis and Metabolic Syndrome complications,” said Head of the Centenary Institute’s ‘Liver Enzymes in Metabolism and Inflammation Program’, Professor Mark Gorrell who collaborated on the research.

“This new discovery is encouraging regarding the safety of those new drugs, and may also help people who are at risk of, or have, coronary plaques,” he said.

The research has been published in the leading international cardiology journal, Cardiovascular Research.

Read the full publication here: https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvaa142/5836831

Read more about the Centenary Institute ‘Liver Enzymes in Metabolism and Inflammation Program’ here: https://www.centenary.org.au/cen_program/liver-enzymes-in-metabolism-and-inflammation-program/

COVID-19 research targets human enzymes

Centenary Institute researchers have examined the critical role of human enzymes and the coronavirus in a newly published scientific review article that explores potential strategies for COVID-19 disease treatment and management.

The review article published in the prestigious ‘Journal of Diabetes’, seeks to explain how the human enzyme dipeptidyl peptidase (DPP4), which is a driver of diabetes severity, could be exacerbating COVID-19.

“COVID-19 is more severe in people who have type 2 diabetes, obesity and related chronic diseases,” says Professor Mark Gorrell (Head of the Centenary Institute Liver Enzymes in Metabolism and Inflammation Program) and senior author of the review article.

“We also see more DPP4 made in people with diabetes, obesity and related chronic diseases. Drugs that target DPP4 enzyme activity are regularly taken by many people for type 2 diabetes. Such drugs may have immune system and cardioprotective effects that could be beneficial in COVID-19 cases,” he says.

The review article notes that DPP4, which is known to be the key receptor for the MERS-coronavirus (Middle East respiratory syndrome) might also be an additional or alternate port of entry for SARS-CoV-2 into human cells.

“COVID-19 is caused by the SARS-CoV-2 coronavirus, which is similar to SARS-CoV and MERS-CoV. Each of these viruses attach to and enter human cells by binding to specific human enzymes,” says Professor Gorrell.

“Recent research suggests that SARS-CoV-2 can bind to both DPP4 and the ACE2 enzyme and so have two ways to infect our lungs and gut. Once we fully understand this process, we may be able to develop a drug that can help disrupt this viral activity,” he says.

Professor Gorrell, an expert in human proteases (enzymes that break down proteins) has recently launched a new research program in response to the growing COVID-19 pandemic.

“TMPRSS2 (Transmembrane protease, serine 2) is essential for SARS-CoV and SARS-CoV-2 infection. This protease activates the viral protein on the coronavirus necessary for virus cell entry at the start of viral infection in the human body,” he says.

“We are looking to develop a selective TMPRSS2 inhibitor that is both effective and very safe using our expertise and a unique drug screening approach. The successful development of such an inhibitor could be utilised as a novel therapy for both past and current, and possibly future, SARS-CoV coronaviruses.”

“I’m optimistic that our research will contribute meaningfully to the global COVID-19 health response,” he says.

Read the full media release here.

Further Information on the Centenary Institute’s coronavirus activity can be found here.

Postgraduate Research Coordinator of the Year 

Professor Mark Gorrell, Head of Centenary’s Liver Enzymes in Metabolism and Inflammation Program has received a Sydney University Postgraduate Representative Association (SUPRA) Postgraduate Research Coordinator of the Year (Medicine) Award for 2019. 

The Award acknowledges outstanding knowledge, commitment and care in higher degree research supervision at the University of Sydney as nominated and judged by research postgraduates. 

“This award is a great pleasure because it is from the students who are my focus in facilitating their navigation of the university system and their career progression to attain a high level training degree,” says Prof Gorrell.