Researchers developing antiviral therapies must race against rapidly mutating viruses.¹ Kent Kirshenbaum, a chemist at New York University, saw stable viral targets as potential solutions. So, he and his team targeted enveloped viruses because these viruses build their lipid membranes using host lipids. As a result, they do not change with mutations to viral nucleic acids. 

In a recent study, Kirshenbaum and his team successfully damaged the membranes of different viruses using engineered peptide-like molecules. Their findings, reported in ACS Infectious Diseases, offer a novel antiviral targeting approach.²

Inspired by how the immune system combats pathogens with antimicrobial peptides, Kirshenbaum and his team turned to synthetic peptoids, which mimic the chemical structures and bioactivities of peptides. When designing and building peptoids, researchers can customize functional groups to increase their longevity in the body. Due to the unique properties of these molecules, Kirshenbaum described the peptoids’ broad-spectrum activity against bacteria, fungi, and viruses as pathogen agnostic. 

Kirshenbaum’s team used three previously discovered linear peptoids and synthesized four new cyclic variations with increased antiviral activity for this study.³ When the team incubated the peptoids with infectious viruses, they effectively disrupted the membranes of all three enveloped viruses: Zika, Rift Valley fever, and chikungunya. Next, the team investigated which lipids were susceptible to peptoid-induced damage, and found that the peptoids specifically targeted phosphatidylserine.

“We've got a situation where molecules are targeting one component of a membrane that's displayed on the exterior of pathogens like viruses but is sequestered from the exterior of our human cell membranes,” Kirshenbaum explained.

Amelia Fuller, a chemist from Santa Clara University who was not involved in the study, said that these findings are a starting point for understanding how peptoids interact in the body as therapeutics. “You can easily swap in and out different [functional group] features to ask really specific and narrow questions about [peptoid] interactions in biological systems.”

For his next step, Kirshenbaum plans to look beyond viruses. By finetuning these peptoids, he hopes to explore their abilities to mimic other biologically active peptides for targeting other pathogens. 

References

  1. Sanjuán R, et al. J Virol. 2010;84(19):9733-9748.
  2. Tate P, et al. ACS Infect Dis. 2023;9(8):1508-1522.
  3. Diamond G, et al. Pharmaceuticals. 2021;14(4):304.