A team of researchers has created peptide-like molecules – "peptoids" – with antiviral properties that could circumvent the naturally occurring antimicrobial peptides' (AMPs) shortcomings. The researchers are trying to turn these newly designed molecules into the basis for an emerging category of antiviral drugs that could treat a broad range of infections, including such disparate illnesses as herpes and COVID-19.
The peptoid structure is based on oligo-N-substituted glycine backbones designed to mimic AMPs. Structurally, instead of the functional group attached to the central carbon, as in standard amino acids, the monomers of these fully synthetic peptoids have the functional group attached to the nitrogen of the amino group.
"The sequence of atoms in the backbone is identical," Annelise Barron, an associate professor of bioengineering at Stanford University, told reporters during a press conference of the American Chemical Society (ACS), whose 2021 annual meeting is occurring in a hybrid of virtual and in-person formats this week.
But "all the side chains are attached one bond over... [and] this makes peptoids completely invulnerable to breakdown."
Barron presented the work at a virtual session on Tuesday.
AMPs are a class of naturally occurring small peptides that are an important part of the innate immune system of different organisms.
They have potent antimicrobial activity and can function against a broad spectrum of pathogens, Gill Diamond, professor of oral immunology at the University of Louisville School of Dentistry, told reporters.
A particularly attractive feature of peptides, Diamond said, is that "microbes don't seem to be able to develop resistance against them."
The reason is that peptides selectively bind to the viral membrane and break the viral envelope apart, thus directly neutralizing the virus.
Like human cells, pathogen membranes are made of a phospholipid bilayer. But pathogen membranes are negatively charged because the phospholipid heads on their membranes differ from those of human cells. The peptoids hone to those negatively charged membranes through electrostatic interaction.
Their direct mechanism allows peptides to inactivate many types of pathogens, even very structurally different viruses, such as HSV-1 and SARS-CoV-2. The only major similarity between the two viruses is that they both are enveloped by a viral membrane.
However, despite the strengths of natural peptides, no one has been able to turn them into a useful therapeutic agent. There are several challenges, and one of them is that in the body, they are rapidly digested by enzymes, which makes them too unstable.
In the work now presented at the ACS meeting, biomimetic peptoids exhibited potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection.
Overall, the team has tested peptoids against more than 50 different strains of microbes in vitro, including pan-resistant bacteria, and shown that they were able to break up their membranes in each case.
Furthermore, the researchers observed no cytotoxicity against primary cultures of oral epithelial cells, indicating specificity for the virus alone.
Barron is now working on structure-activity relationships of the antiviral peptoid candidates. In addition to herpes, HSV and SARS-CoV-2, the team has also found promising new results indicating antiviral peptoid activity against rhinovirus and hepatitis B virus. Barron expects clinical trials on the peptoids to begin within the next year. If the clinical trials are successful, peptoids could act as both prophylactics and therapeutics for COVID-19.
Barron is the co-founder of Maxwell Biosciences, which has developed the CLAROMER anti-infective platform based on these biomimetic peptoids. Maxwell's CLAROMER platform mimics the activity of the natural human cathelicidin, LL-37 AMP.
LL-37 is itself "remarkable," Barron said. It is primarily deployed by macrophages and leukocytes but is also produced in epithelial tissues as the first line of defense against infection. LL-37 selectively targets and destroys invading pathogens before they get a chance to infect cells and colonize tissues. Its target range is extremely broad, encompassing simultaneously antiviral, antibacterial, antifungal, antiparasitic, anticancer and antibiofilm activity.
Maxwell, she said, is planning to enter clinical trials by 2022. If those trials pan out, the manufacturing cost of peptoids, although still higher than for small molecules, would be substantially lower that for peptides.
The reagents needed to make peptoids, she said, are cheaper than those for peptides. "But both must be purified, which is inherently expensive."