Antiviral strategy using synthetic peptoid has promising implications for fighting infection

By James DuckerAug 24 2021Reviewed by Emily Henderson, B.Sc.

Scientists have manufactured a synthetic form of peptide to combat viral infections, with successful tests already conducted on HSV-1 as well as SARS-CoV-2, showing no signs of cytotoxicity and improving the treatment of viral infections, with many potential applications. This research was presented at a meeting of the American Chemical Society.

Peptoids. Image Credit: Maxwell Biosciences

Harnessing natural defenses to prevent harmful infections

The human immune system produces peptides to fight harmful viruses as well as other pathogens in the body. However, as a defense, peptides do not last long and researchers have therefore focused on developing stronger, more stable, peptide mimics.

These mimics include small synthetic molecules known as peptoids, and a new study that will be presented during the fall meeting of the American Chemical Society (ACS), has shown that one particular peptoid, LL-37, is a promising candidate for antiviral treatments.

Annelise Barron, Ph.D., one of the project’s principal investigators, describes the mechanism: “In the body, antimicrobial peptides such as LL-37 help keep viruses, bacteria, fungi, cancer cells and even parasites under control,” and since peptides degrade easily due to the rapid action of enzymes, she and her colleagues mimicked the key biophysical attributes of LL-37 in smaller, more stable molecules called peptoids.

Peptoids are easy to make, and unlike peptides, they’re not rapidly degraded by enzymes, so they could be used at a much lower dose.”

Annelise Barron, Ph.D

Instead of the short sequences of amino acids with side chains bonded to carbon atoms found in peptides, the side chains in peptoids are linked to nitrogens in the molecular backbone, forming a structure that resists enzymatic clearance.

Peptoids were first developed in 1992 by Chiron Corp.’s Ronald Zuckermann, Ph.D., who later became Barron’s postdoctoral adviser. These peptide mimics are simple, inexpensive, and less time-consuming to manufacture using automated synthesizers and readily available chemicals.

To further explore the action of peptoids, Barron, Zuckermann, Gill Diamond, Ph.D., of the University of Louisville and others founded Maxwell Biosciences, allowing them to design effective peptoids used as clinical candidates to treat viral infections.

A less toxic, more effective, peptoid to combat a range of viruses

In recent studies, the team reported that their newly manufactured peptoid sequences are able to inactivate compounds of SARS-CoV-2, the virus causing COVID-19, and herpes simplex virus-1 (HSV-1), which causes oral cold sores in lab-cultured cells.

Now, the researchers are reporting in vivo results that demonstrate the peptoids prevent herpes infection in mice when simply dabbed on their lips. Further studies are currently considering the duration of the peptoids’ effectiveness against HSV-1 that is resistant to acyclovir, which is the best current U.S. Food and Drug Administration-approved antiviral treatment for this condition, Barron says.

Additionally, the team is also getting ready to test peptoids for activity against SARS-CoV-2 in mice. “COVID-19 infection involves the whole body, once somebody gets really sick with it, so we will do this test intravenously, as well as looking at delivery to the lungs,” Barron says.

Further work is also ongoing on the application of peptoids to treat ear and lung infections. Barron has also sent peptoid samples to experts in other labs to test against a range of viruses, with promising results in lab dish studies against influenza, the cold virus, and hepatitis B and C.

Additional research groups are also experimenting on whether the peptoids can be used as effective antifungals for airways as well as an anti-infective coating for optical contact lenses, catheters, and implanted hip and knee joints.

Such a diverse range of applications demonstrates the extent of potential peptoid application. And to better understand its mechanism, Diamond and Barron are studying the process of how the peptoid can pierce and break the viral envelope and also bind to the virus’ RNA or DNA.

This would inactivate the virus particles completely, which contrasts to standard antivirals, which slow viral replication but still allow viruses to infect host cells.

Looking forward, Barron expects clinical trials to begin within the year. If successful, she describes how peptoids could be administered as a preventative — for instance, before air travel to protect a passenger from COVID-19 — or after an infection begins, such as when a person feels the onset of an oncoming cold sore.