Blue peptidoids (left) penetrate the protective coating of viruses, causing their disintegration or inactivation (right). Maxwell Biosciences
The immune system uses peptides to combat viruses and other pathogens in addition to white blood cells and antibodies. Researchers are working to develop stable peptide mimics. Synthetic peptides can be used to strengthen this defense, but they don't last very long in the body. Scientists have reported success with mimics, known as peptoids, in treating animals with herpesvirus infections. These tiny synthetic molecules could be used to cure or prevent many types of infections, including COVID-19.
At the American Chemical Society's fall meeting, the researchers will present their findings.
Annelise Barron Ph.D. is one of the principal investigators for the project. She says that antimicrobial peptides like LL-37 "help keep viruses, bacteria and fungi under control in the body." Peptides are fast cleared by enzymes so they're not good drug candidates. Instead, she and her coworkers replicated the biophysical properties of LL-37 by making smaller, more stable molecules called "peptoids". Barron, a Stanford University student, says that peptidoids are simple to make. They are not quickly degraded by enzymes like peptides so could be used in a lower dosage."
A peptidide is a short sequence of amino acids that has side chains that are bonded to carbon atoms. Enzymes can easily break down this structure. Peptoids have side chains that are linked to the nitrogens in their molecular backbone. This creates a structure that is resistant to enzymes. These side chains were created by Ronald Zuckermann of Chiron Corp. in 1992. He was later Barron's postdoctoral advisor. Peptoids, unlike other types of peptide imitations, require complex, multi-step organic chemical chemistry to create. They are easy to make and affordable to make using an automated synthesizer with readily available chemicals. They can be made in the same way as bread machines.
Maxwell Biosciences was founded by Drs. Barron, Zuckermann and Gill Diamond of the University of Louisville. The company's goal is to develop peptoids that can be used to treat or prevent viral infections. Their latest peptoid sequences were recently published. They are less toxic than the previous ones. The compounds were able to inactivate SARS-CoV-2 (which causes COVID-19) and herpes simplexvirus-1 (HSV-1), making them ineffective in infecting cultured cells of human beings.
The researchers now report in vivo results showing that peptoids prevented the spread of herpes in mice by rubbing their lips with the oil. Diamond's group is currently conducting further experiments to confirm these mouse results. In addition, they will investigate the peptoids' effectiveness against HSV-1 strains that are resistant to acyclovir, the best current U.S. Food and Drug Administration-approved antiviral treatment for this condition, Barron says.
Researchers are also preparing to test peptoids against SARS-CoV-2 infection in mice. Barron states that COVID-19 infection can affect the entire body. Once someone is really sick, we will test the peptoids intravenously and also look at delivery to the lungs.
These antimicrobial molecules may have other uses. Stanford is currently investigating their potential impact on ear infections and lung diseases. Barron sent peptoid samples out to other experts to be tested against a variety of viruses. The results were promising in lab dish studies against influenza and the cold virus. Peptoids are being tested in other labs as antifungals for the airways and the stomach, as well as as anti-infective coatings on contact lenses, catheters, and implanted knee and hip joints.
Diamond and Barron are currently studying the mechanism of these broad-spectrum compounds. They appear to penetrate and break down the viral envelope as well as bind to the virus’ RNA and DNA. Barron states that this multi-pronged mechanism inactivates the virus. This is in contrast to standard antivirals which slow down viral replication, but still allow viruses infect cells. It makes it less likely for pathogens to develop resistance.
Barron anticipates that clinical trials will begin in the next year. Peptoids, if successful, could be used as a preventative. For example, they could be administered before an individual travels to COVID-19-free. Or after an infection has taken hold.
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More information: Antimicrobial peptoids have potent antiviral activity against HSV-1, and SARS-CoV-2. ACS Fall 2021.
