Developing small-molecule compounds that can disrupt the normal functioning of the inflammation-promoting CARD9 protein could be a way to treat bowel diseases, a study reports.
The protein helps the body fight fungal infections. In doing so, it generates inflammation that can lead to or worsen an inflammatory bowel disease, however.
The research, “Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease,” was published in the journal PNAS.
Scientists often conduct Genome-Wide Association Studies to see if there is a genetic component to a disease. Unfortunately, most of the time, they are unable to translate the information into therapies.
A research team decided to try using the genetic information available on inflammatory bowel diseases, or IBDs, to develop a treatment for them.
Gene sequencing studies have shown that mutations of the CARD9 gene, which generates a protein that is also called CARD9, can protect against an IBD.
CARD9 protein plays a role in inflammation by activating the NF-κB–inflammatory pathway. The protective variant of the CARD9 gene, called CARD9Δ11, does not promote inflammation, however. The CARD9Δ11 mutation produces CARD9Δ11 protein.
Previous research showed that CARD9 protein promotes inflammation by binding with another protein, TRIM62. The CARD9Δ11 protein is incapable of binding with TRIM62, preventing inflammation.
These findings prompted researchers to hypothesize that small molecules that were able to interfere with the binding of CARD9 and TRIM62 could generate the protective effect that the CARD9Δ11 protein produces.
To pursue their hypothesis, researchers came up with a way to measure the disruption of the protein-protein interaction between CARD9 and TRIM62. They used this yardstick to analyze 132,813 small molecules that might be able to disrupt CARD9–TRIM62 interaction.
They discovered that four structurally related compounds called BRDs were able to bind with the CARD9 protein, preventing it from interacting with TRIM62. This prevented CARD9 from promoting inflammation.
Researchers then used lab experiments to show that their lead compound, BRD5529, could reduce CARD9 inflammatory signaling. Their experiments involved two immune-system cell lines. The “small molecules directly bind CARD9 in vitro [in a lab] to inhibit its association with TRIM62,” the team wrote.
The strategy the team pursued is intriguing because it’s a precision approach. It shuts down only one immune pathway. Most immuno-modulatory compounds affect multiple pathways.
A key lesson of the study was that understanding the genetic basis of diseases can reveal pathways that researchers can target to develop therapies. In this instance, the scientists demonstrated that, by preventing inflammation, small-molecule inhibitors can protect patients against an IBD.