Study by U of T and American researchers could lead to anti-inflammatory treatments, including for COVID-19

Chris McCulloch sits at a table with a colleague
Chris McCulloch (right), a professor at the Faculty of Dentistry, was a co-lead of a study that found the combination of two peptides can penetrate a cell’s membrane to dampen an acute inflammatory response (photo by Jeff Comber)

A collaboration between the University of Toronto’s Faculty of Dentistry and the National Jewish Hospital in Denver has yielded a new discovery that could be useful to combat inflammation and shows promise in fighting acute respiratory illnesses such as COVID-19.

Called TAT CARMIL1, the discovery is a combination of two naturally occurring peptides that work together to penetrate a cell’s membrane to dampen an acute inflammatory response. In the study, the peptide reduced collagen degradation by up to 43 per cent. If deployed early enough, the researchers say, the peptide could allay some of the worst damage caused by acute inflammatory responses such as cytokine storms – a natural defence response to an acute infection that is sometimes associated with COVID-19.

Cytokines are a type of immune response cell, but when the body becomes overwhelmed by infections such as those caused by influenza, H1N1 or COVID-19, it can release an unregulated flood of cytokines into the body. In those instances, infection-busting cytokines can cause severe damage in the body – everything from holes in the lung tissue to vascular damage and blot clots, with the most acute cases causing death.

Greg Downey, a pulmonologist and professor in the department of medicine at the National Jewish Hospital who co-authored the study, published recently in Cell Reports, says he was excited by the peptide discovery.

“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 says.

Here’s how it works: the peptide combines a segment of a naturally occurring protein, CARMIL1, with a peptide “vehicle,” TAT, that brings the CARMIL1 directly into the cell. That enables the CARMIL1 to calm the inflammatory storm. The CARMIL peptide effectively blocks a family of cytokines, called interleukin-1 from signalling and reproducing in vast quantities.

What makes the discovery so unique is how precise it is. The TAT CARMIL1 peptide targets two receptors, sticking to both the cell’s surface and its cell substrate, where it adheres to other cells.

“The two receptors necessary for it to work supplies an unusual level of specificity,” explains Chris McCulloch, a professor at the Faculty of Dentistry and a co-lead of the study. “We think the unusual nature of this pathway might restrict its side effects.” 

That could make the peptide an unusually strong candidate as 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.

“This is a precise pathway to deal with a precise issue,” says Downey.

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.

Still, Downey cautions, more work needs to be done. The initial study shows that the storm-stopping peptide is most effective when it is applied as an early intervention. That, says Downey, is impractical: “In the clinical world, the reality is that you don’t have that luxury.” 

The research was supported by the Canadian Institutes of Health Research, among others.

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