Blocking one enzyme could help treat many chronic disorders

July 27, 2018      By Catharine Paddock PhD

Researchers have identified an enzyme that plays a key role in a biological mechanism common to many chronic inflammatory disorders.

Targeting one enzyme may lead to new treatments for many conditions.

The discovery — which has been reported in a paper now published in the journal Nature — could lead to new drugs for treating diverse inflammation-related diseases, ranging from Parkinson's and Alzheimer's to osteoarthritis and cancer.

The enzyme is called cytosine monophosphate kinase 2 (CMPK2) and it activates NLRP3, an inflammation-triggering molecule, or inflammasome.

Scientists already knew that finding a way to block NLRP3 without affecting other inflammasomes could lead to new treatments for many inflammatory conditions.

"Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases," note the authors.

But without a clear understanding of the molecular pathways involved in triggering NLRP3, it was not possible to design drugs that specifically block it.

The 'cost and benefit' of inflammation

Inflammation is an altered biological state of cells and tissues that occurs in response to infectious agents, mechanical injury, or stress. The response is complex and triggered by inflammasomes.

The state of inflammation brings potential benefits in that it can heal, restore health, and secure survival. But this happens at a cost.

During inflammation, there is a "decline in the normal function" of the affected cells and tissues while the threat is eliminated or the repair takes place.

In short-term conditions, the benefits of inflammation outweigh the costs. The infection clears, the wound is healed, and normal tissue function is restored.

But when the state of inflammation persists, the costs outweigh the benefits. For some reason, the "stimulating trigger cannot be removed" and a chronic inflammatory disease develops.

CMPK2 blockers

During the state of inflammation, there is a sharp rise in a hormone called interleukin 1 beta (IL-1B). The hormone is important for many cell events that occur during inflammation, including proliferation and death.

Inflammasomes control the production and release of IL-1B. NLRP3 is most active in this process. It senses diverse stimuli from noxious threats to tissue changes. These range from silica dust and asbestos to the microcrystals of uric acid that cause inflammation in gout.

In their study, Prof. Michael Karin — from the University of California, San Diego — and team focused on CMPK2 and the key role that the enzyme plays in triggering NLRP3 in sparking production of IL-1B and the subsequent development of chronic inflammatory conditions.

CMPK2 is a nucleotide kinase. Drug developers have already "successfully targeted" some of the enzymes in this group.

Prof. Karin suggests that CMPK2 blockers could reduce pain, inflammation, and tissue damage in osteoarthritis and gout, as well as slow the development of Parkinson's and Alzheimer's diseases.

"I predict that specific inhibitors of CMPK2 can be easily and rapidly developed."

Prof. Michael Karin

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