Along with antibodies and white blood cells, the immune system fights viruses and other invaders with peptides. Because synthetic peptides do not persist in the body, researchers are developing stable peptide mimics.
In a new study, scientists claim success in treating animals infected with herpes virus using mimics known as peptoids. These small synthetic compounds have the potential to eventually treat or prevent a wide variety of illnesses, including COVID-19.
“In the body, antimicrobial peptides such as LL-37 help keep viruses, bacteria, fungi, cancer cells and even parasites under control,” says Annelise Barron, one of the project’s principal investigators.
However, because peptides are rapidly degraded by enzymes, they are not excellent therapeutic candidates. Rather than that, she and her colleagues replicated LL-37’s fundamental biophysical properties in smaller, more stable molecules called peptoids.
“Peptoids are easy to make,” says Barron.
“And unlike peptides, they’re not rapidly degraded by enzymes, so they could be used at a much lower dose.”
Peptides are short sequences of amino acids with side chains attached to the carbon atoms in the backbone of the molecule. Enzymes are capable of quickly dismantling this structure. In peptoids, the side chains are connected to nitrogens in the molecular backbone, resulting in an enzyme-resistant structure. They were first developed in 1992 by Ronald Zuckermann, Ph.D., of Chiron Corp., who later served as Barron’s postdoctoral adviser. Unlike other peptide mimics, which require arduous, multi-step organic chemistry to generate, peptoids are straightforward and inexpensive to synthesise using an automated synthesiser and widely available ingredients, she explains.
“You can make them almost as easily as you make bread in a bread machine.”
In the lab trial, the compound inactivated the SARS-CoV-2 virus, which produces COVID-19, and herpes simplex virus-1 (HSV-1), which causes oral cold sores, in cultured human cells.
The researchers now publish in vivo results demonstrating that when rubbed on the lips of mice, peptoids effectively prevented herpes infections. Diamond and his colleagues are currently undertaking additional trials to corroborate the mice findings. Additionally, they will assess the peptoids’ efficacy against HSV-1 strains resistant to acyclovir, the most effective antiviral medication currently licenced by the United States Food and Drug Administration, Barron says.
“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.
However, these antimicrobial compounds may have a plethora of additional applications. Stanford researchers are currently investigating their effect on ear and lung infections. And Barron has sent peptoid samples to experts in other labs for virus testing, with encouraging results against influenza, the common cold virus, and hepatitis B and C in laboratory dish trials.
“In their in vitro studies, a team found that two of the peptoids were the most potent antivirals ever identified against MERS and older SARS coronaviruses,” Barron says.
Other laboratories are evaluating peptoids as antifungals for the airways and gut, as well as antimicrobial coatings for contact lenses, catheters, and implanted hip and knee joints.
The team is examining the mechanism of action of these broad-spectrum molecules. They appear to penetrate and disrupt the viral envelope, as well as bind to the virus’ RNA or DNA. This multipronged approach has the advantage of inactivating the virus, as opposed to typical antivirals, which limit viral replication yet allow viruses to infect cells, Barron explains. Additionally, it reduces the likelihood of infections developing resistance.