Anti-inflammatory TAT CARMIL1 discovery offers hope for COVID-19

Peptide combination could be effective in reducing damage caused by COVID-19 infections

TORONTO, Ontario—A collaboration between the University of Toronto’s Faculty of Dentistry and the National Jewish Health hospital in Denver — the top-ranked respirology research hospital in the U.S. — has yielded a discovery that could be useful to combat inflammation. It shows promise in fighting acute respiratory illnesses like COVID-19.
 
The new study, published July 30 in Cell Reports, was funded by a grant from the Canadian Institutes of Health Research. The discovery — called TAT CARMIL1 — is a combination of two naturally occurring peptides that, when combined, work together to penetrate a cell’s membrane in order to dampen an acute inflammatory response.
 
In this first ex vivo study, the peptide reduced collagen degradation by up to 43 percent. If deployed early enough, the researchers said that the peptide could alleviate some of the worst damage caused by acute inflammatory responses.
 
Acute infections can cause inflammatory responses known as cytokine storms. This storm is a natural defense response — when the body is overwhelmed by infections such as those caused by influenza, H1N1 or COVID-19, it can release an unregulated flood of cytokines into the body. Cytokines can cause severe damage in the body, from holes in the lung tissue to vascular damage and blood clots. The most acute cases can cause death.
 
Dr. Greg Downey, who is pulmonologist, professor and executive vice president of academic affairs in the Department of Medicine at the National Jewish Hospital, co-authored the study. He said he is excited about the peptide discovery.
 
The peptide combines a segment of a naturally occurring protein, CARMIL1, with a peptide “vehicle,” TAT, that brings the CARMIL1 directly into the cell. This enables CARMIL1 to dampen the inflammatory storm. The CARMIL peptide effectively blocks interleukin1 from signaling and reproducing in vast quantities.
 
“There are a lot of people looking at these areas, but this study gives the first indication of how these CARMIL proteins are involved with this pathway,” Downey added.
 
The discovery is unique because of its precision. The TAT CARMIL1 peptide targets two receptors, sticking to both the cell’s surface and its cell substrate.
 
“The two receptors necessary for it to work supplies an unusual level of specificity. We think the unusual nature of this pathway might restrict its side effects,” explained Chris McCulloch, professor at the Faculty of Dentistry and a co-lead of the study.
 
The peptide could make an unusually strong candidate for a potential drug target. Drugs designed with this peptide would need to target cells at both receptors, narrowing the potential field of candidates from tens of thousands to hundreds.
 
Downey pointed out that “This is a precise pathway to deal with a precise issue.”
 
Next, the team hope to track the peptide’s success in in vitro models. Given the broad applicability of the peptide — which can be combined with other drugs, such as cancer or arthritis drugs — the discovery could one day become a useful ally in the fight against all types of inflammation.
 
More work needs to be done, Downey cautioned. The initial study shows that the storm- stopping peptide is most effective when it is applied as an early intervention, which is impractical. “In the clinical world, the reality is that you don’t have that luxury,” Downey concluded. 
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