CMPK2 inhibitor could lesson symptoms of common illnesses

Inhibitors of CMPK2 could be rapidly developed to treat common and currently untreated diseases.

Despite being part of the body’s natural healing process, inflammation can lead to various diseases from cancer to Alzheimer’s disease.

Researchers at the University of California, San Diego School of Medicine identified a signalling pathway which activates the NLRP3 inflammasome in severe cases of chronic inflammatory disorders.

Inflammasomes are multiprotein oligomer complexes which are responsible for activating inflammatory responses to signals generated by cells under stress, through tissue injury or infectious organisms. They contain sensor proteins that respond to these signals.

Dr Zhenyu Zhong, first author of the study said, “It has been obvious for some time that, when available, drugs that turn off the NLRP3 inflammasome, but not other inflammasomes, will be very useful for treating a variety of inflammatory disorders, from osteoarthritis to Alzheimer’s disease and cancer.

“Until recently, it was not clearly understood how environmental stress and tissue injury activate the NLRP3 inflammasome and, without such knowledge, it was impossible to rationally design specific inhibitors of the NLRP3 inflammasome.”

Interleukin 1β (IL-1β) is a cytokine protein important in mediating the inflammatory response and is also involved in other activities, such as cell differentiation, proliferation, and apoptosis. Ordinarily, it is produced in very low amounts, but levels are increased when the body endures injury, infection, environmental stress or chronic inflammation. The production and secretion of IL-1β is controlled by inflammasomes.

One sensor protein, NLRP3, is responsible for inflammasome activation and the production of IL-1β in response to tissue injury, or microparticles such as asbestos and silica dust. Activators of NLRP3 include microcrystals of cholesterol or uric acid, which trigger the inflammation associated with atherosclerosis and gout.

Dr Zhong and his team worked with Professor of Pharmacology and Pathology, Dr Michael Karin. They described the critical role that cytosine monophosphate kinase 2 (CMPK2) plays in activating NLRP3 and thus IL-1β production, and its consequences in chronic inflammatory disorders.

Prof Karin said, “I predict that specific inhibitors of CMPK2 can be easily and rapidly developed. Once available such compounds may provide us with new treatments for many diverse untreatable and common illnesses, including osteoarthritis, Alzheimer’s disease and lung cancer.”

He went on to mention that CMPK2 inhibitors may reduce inflammation, pain and tissue damage in arthritis and gout. In Parkinson’s and Alzheimer’s inhibitors may slow loss of cognitive function and progression of the diseases.

“Unlike IL-1β antibody, which blocks IL-1β that is produced in response to bacterial infections, the CMPK2 inhibitor will prevent IL-1β induction in response to tissue injury or micro particles,” said Prof Karin.

The study was published in Nature.