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A switch for autoimmunity

by Meredith Jackson

When a virus or bacteria comes calling, protein “sensors” in your cells can detect the invader’s DNA and activate inflammatory responses to prevent infection. One such sensor is cGAS (cyclic GMP-AMP synthase).

Normally, cGAS is an asset – something you definitely want to be working for you. However, abnormal responses to intracellular DNA can lead to hyper-inflammatory or autoimmune disorders such as lupus. Turning cGAS off may actually help treat this disease.

Manuel Ascano Jr., Ph.D., and colleagues now report the discovery of a class of compounds that can inhibit cGAS. One “chemically improved” compound, RU.521, showed potent and selective inhibition of cGAS activity and lowered inflammatory signaling molecules in immune cells in a mouse model of an autoimmune disease.

Reporting Sept. 29 in the journal Nature Communications, the researchers concluded that RU.521 will help scientists learn more about the biological roles of cGAS and as a “molecular scaffold” may pave the way for development of future therapies for autoimmune disorders.

This research was supported in part by grants from the National Institutes of Health (GM119569, GM065086, GM104962, CA008748), the Vanderbilt University Department of Biochemistry, and Rockefeller University Robertson Therapeutic Development Funds.

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