Scientists Develop Better Ways To Block Viruses That Cause Pediatric Respiratory Infections

By designing short chunks of proteins or peptides that can prevent the Madison-human parainfluenza virus from adhering to cells, researchers have developed a rodent model method aimed at maintaining the health of children. It has improved.

Human parainfluenza virus (HPIV) is the leading cause of childhood respiratory infections and is responsible for 30% to 40% of illnesses such as croup and pneumonia. The virus also affects the elderly and people with weakened immunity.

To make people sick, HPIV needs to latch into cells and inject genetic material to start the production of new viruses. HPIV3 is the most prevalent of these viruses. Currently, there are no approved vaccines or antivirals for HPIV3 infections in people.

In a study led by Sam Gellman’s lab in the Department of Chemistry at the University of Wisconsin-Madison, and Anne Moscona and Matteo Porotto’s lab at Columbia University, researchers build on years of research into peptide treatment to produce something that can block peptide treatment. did. HPIV3 connection process.

Researchers released their findings on April 7 Journal of the American Chemical Society..

HPIV uses a special fusion protein that resembles three bottle openers arranged side by side to invade a host cell. Early studies by the Moscona-Porotto lab showed that scientists could introduce a partial mass of this cork bottle opener protein from HPIV3 into the virus and prevent cork bottle opener from facilitating the infectious process. I did. The peptide itself is a cork bottle opener, which essentially zips the virus bottle opener to create a tight bundle in the form of six cork bottle openers.

The new peptide lasts longer in the body and is about three times more effective in stopping infection in models of rodent disease than in its original form.

The research team began by designing the original peptide to be more resistant to protein-digesting enzymes in the body, which can easily shred proteins to make them useless. So Gellman Labs turned to unusual building blocks to create harder peptides.

Cells make proteins from alpha amino acids. However, chemists can create beta amino acids. Beta amino acids are similar, but with extra carbon atoms. When peptides use these beta amino acid building blocks, they often take different shapes due to the extra atoms. This can help the peptide hide from protein digestive enzymes and survive longer.

However, researchers also knew that if the shape of the peptide changed significantly as a result of these abnormal components, it might not lock with the HPIV cork bottle opener fusion protein.

That’s why decades of experience in testing and modifying beta-amino acid-containing peptides in Gellman Labs became important.

“I knew which side of the peptide was bound to that protein target, so I knew that I could only modify residues that weren’t directly involved in viral protein binding,” said a postdoctoral fellow in the lab. One Victor Outlaw said. One of the co-lead authors of the report. Laboratory tests have shown that carefully modified peptides are still strongly bound to viral proteins.

In another improvement pioneered by the Moscona-Porotto lab, scientists linked peptides to cholesterol molecules. The addition of this fat helps the peptide slide into the greasy cell membranes, where it can best block the virus.

“Our hypothesis was that the combination of beta amino acids and cholesterol would enhance antiviral effects,” says Outlaw. A peptide that lasts longer in the body.

As the research team wanted, when cotton rats were given new peptides, they lasted much longer in the lungs than previous versions, thanks to their resistance to enzymatic digestion. The peptide was delivered to the rat nose.

To test how well the peptides worked to prevent infection, cotton rats received new peptides prior to exposure to HPIV3. Compared to animals that were not given antiviral peptides, animals that were given the improved peptides had one-tenth the virus in their lungs.

Also, harder peptides reduce viral load by about one-third compared to enzymes-sensitive peptides, and the ability of new peptides to avoid digestion in the body helps prevent infection better. It suggests that.

This approach has not yet been tested in humans and researchers need to further improve and test the system, but it offers new strategies for potentially preventing or treating these common infections. ..

The collaborative research is now aimed at producing second-generation peptides that will last longer in the body. They also want to test how well modified peptides can block infections by related viruses. That additional study has the potential to bring peptide therapy closer to clinical trials.

“This was a great luck with a group of people with complementary needs and abilities,” says Gellman. “It was a really great joint effort.”