New antivirals possible against COVID-19, herpes

In addition to antibodies and white blood cells, the immune system deploys peptides to fight viruses and other pathogens. Synthetic peptides could strengthen this defense but do not last long in the body, so researchers are developing stable peptide mimics. Today, scientists report that they have successfully used mimics known as peptoids to treat animals infected with the herpes virus. These small, synthetic molecules could one day cure or prevent many types of infections, including COVID-19.

The researchers will present their findings at the American Chemical Society (ACS) fall meeting.

“In the body, antimicrobial peptides such as LL-37 help control viruses, bacteria, fungi, cancer cells and even parasites,” says Annelise Barron, Ph.D., one of the leading researchers. of the project. But peptides are quickly eliminated by enzymes, so they are not ideal drug candidates. Instead, she and her colleagues mimicked the main biophysical attributes of LL-37 in smaller, more stable molecules called peptoids. “Peptoids are easy to make,” says Barron, who is at Stanford University. “And unlike peptides, they are not rapidly broken down by enzymes, so they could be used at a much lower dose.”

Peptides are made up of short sequences of amino acids, with side chains attached to carbon atoms in the backbone of molecules. This structure is easily broken down by enzymes. Rather, in peptoids, the side chains are linked to nitrogen in the molecular skeleton, forming a structure that is resistant to enzymes. They were first created in 1992 by Ronald Zuckermann, Ph.D. of Chiron Corp., later Barron’s postdoctoral advisor. Unlike other types of peptide mimics that require laborious, multistep organic chemistry to produce, peptoids are simple and inexpensive to make with an automated synthesizer and readily available chemicals, she says. “You can make them almost as easily as you bake bread in a bread machine.”

Barron, Zuckermann, Gill Diamond, Ph.D., University of Louisville and others founded Maxwell Biosciences to develop peptoids as clinical candidates to prevent or treat viral infections. They recently reported results with their latest peptoid sequences, which were designed to be less toxic to humans than previous versions. In the lab dishes, the compounds inactivated SARS-CoV-2, which causes COVID-19, and the herpes simplex-1 virus (HSV-1), which causes oral cold sores, rendering viruses incapable of infecting human cells in culture.

Today, researchers are reporting in vivo results showing that peptoids safely prevented herpes infections in mice when they were swabbed on their lips. Diamond’s team is conducting additional experiments to confirm the mouse results. In addition, they will study the effectiveness of peptoids against strains of HSV-1 resistant to acyclovir, the best antiviral treatment currently approved by the United States Food and Drug Administration for the disease, said Barron.

Researchers are also preparing to test the activity of peptoids against SARS-CoV-2 in mice. “COVID-19 infection involves the whole body, once someone is really sick of it, so we will do this test intravenously, as well as administration to the lungs,” Barron said.

But these antimicrobial molecules could have many other applications. Work is underway at Stanford to explore their impact on ear and lung infections. And Barron sent peptoid samples to experts in other labs to test them against a range of viruses, with promising results in lab studies against the flu, the common cold virus, and hepatitis B and C. ” In their in vitro studies, a team found that two of the peptoids were the most potent antivirals ever identified against MERS and the former SARS coronaviruses, “Barron said. Other labs are testing peptoids as respiratory antifungals. and intestine and as anti-infective coatings for contact lenses, catheters and implanted hip and knee joints.

Diamond and Barron are studying how these broad spectrum compounds work. They appear to pierce and break the viral envelope and also bind to the RNA or DNA of the virus. This multi-pronged mechanism has the advantage of inactivating the virus, unlike standard antivirals, which slow viral replication but still allow viruses to infect cells, says Barron. It also makes it less likely that pathogens could develop resistance.

Barron expects clinical trials to begin within the year. If successful, she says, the peptoids could be given as a preventative measure – for example, before an airplane trip to protect a passenger from COVID-19 – or after an infection has set in, such as when a person feels the telltale tingling of an oncoming cold sore. .

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More information:
Potent Antiviral Activity Against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids, ACS Fall 2021.