Scientists from the Wrocław University of Science and Technology in southwestern Poland and the American biotechnology company Genentech developed experimental compounds that target cells undergoing pyroptosis, a rapid form of cell death that causes inflammation.
The results were published in the journal Nature.
Pyroptosis is part of the body’s defense against infections and other threats. During the process, enzymes called inflammatory caspases cut a protein called gasdermin D.
Fragments of the protein then form pores in the cell membrane. The pores allow inflammatory signals to leave the cell and alert the immune system. The cell swells and eventually ruptures.
Although the process helps fight infections, excessive pyroptosis can increase inflammation and damage tissue. It has been linked to conditions including sepsis, acute respiratory distress syndrome and COVID-19.
Scientists have long tried to stop pyroptosis by blocking caspases. Previous inhibitors also entered healthy cells, however, potentially interfering with enzymes involved in other important biological processes.
The Wrocław and Genentech teams took the opposite approach. They designed compounds that penetrate intact cell membranes poorly. The inhibitors enter cells only after pyroptosis has begun and the first gasdermin D pores have appeared.
Once inside, the compounds block caspases and prevent additional pores from forming. The cell’s natural membrane-repair system can then remove the existing damage.
"The project’s most important discovery was demonstrating that pyroptosis can be stopped even after it has begun," said Katarzyna Groborz, who developed the initial inhibitors during her doctoral research in Wrocław and later continued the work at Genentech.
"We showed that there is a short therapeutic window during which caspase inhibition interrupts this process and enables cells to regain their ability to grow and divide," she added.
In one experiment, some rescued cells continued growing for 12 days. The inhibitors also worked when administered several hours after pyroptosis had started.
Marcin Poręba of the Wrocław University of Science and Technology said the key discovery followed an unexpected observation. A compound that could barely cross a healthy cell membrane was still able to stop a process occurring inside a damaged cell.
Rather than dismissing the result, the researchers concluded that pyroptosis itself had opened a route for the compound through the membrane.
The team studied two experimental inhibitors, KGR-3 and KGR-53P. In laboratory tests, KGR-3 blocked pyroptosis triggered by inflammatory caspases and reduced the release of inflammatory signals.
KGR-53P was also tested in mice. Animals that received the compound had substantially lower blood levels of interleukin-1 beta and interleukin-18, two proteins associated with inflammation.
The chemical and enzyme research began at the Wrocław University of Science and Technology’s Faculty of Chemistry. Poręba's team developed the design principles for the inhibitors, created a library of about 100 compounds and examined their interactions with caspases.
Genentech researchers conducted advanced cellular studies, pharmacokinetic tests and animal experiments.
The scientists cautioned that KGR-3 and KGR-53P remain research compounds and require further development. The findings do not mean that a treatment for sepsis or other inflammatory diseases is ready for use.
The discovery could, however, provide a basis for more precise therapies that target cells already undergoing excessive pyroptosis while limiting effects on healthy cells.
(rt/gs)
Source: naukawpolsce.pl