Next-generation antivirals could target virus membranes

Illustration of a virus

Researchers have shown that a group of novel molecules inspired by our own immune system inactivates viruses like Zika and chikungunya, and could help overcome antiviral resistance.

“We found an Achilles heel of many viruses: their bubble-like membranes. Exploiting this vulnerability and disrupting the membrane is a promising mechanism of action for developing new antivirals,” said Kent Kirshenbaum, Professor of Chemistry at New York University (NYU) and the study’s senior author.

Viruses have different proteins on their surfaces that are often the targets of therapeutics like monoclonal antibodies and vaccines. But targeting these proteins has limitations, as viruses can quickly evolve, changing the properties of the proteins and making treatments less effective.

“There is an urgent need for antiviral agents that act in new ways to inactivate viruses,” said Kirshenbaum. “Ideally, new antivirals won’t be specific to one virus or protein, so they will be ready to treat new viruses that emerge without delay and will be able to overcome the development of resistance.

“We need to develop this next generation of drugs now and have them on the shelves in order to be ready for the next pandemic threat – and there will be another one, for sure.”

A study of seven peptoids

Our innate immune system combats pathogens by producing antimicrobial peptides. Most viruses that cause disease are encapsulated in membranes made of lipids, and antimicrobial peptides work by disrupting or even bursting these membranes.

While antimicrobial peptides can be synthesised in the lab, they break down easily and can be toxic to healthy cells. Instead, scientists have developed synthetic materials called peptoids, which have similar chemical backbones to peptides but are better able to break through virus membranes and are less likely to degrade.

The NYU team studied the antiviral effects of seven peptoids against four viruses: three enveloped in membranes (Zika, Rift Valley fever, and chikungunya) and one without (coxsackievirus B3).

“We were particularly interested in studying these viruses as they have no available treatment options,” said Patrick Tate, a chemistry PhD student at NYU and the study’s first author.

Recognition of phosphatidylserine

Lipids are acquired from the host to form membranes. One such lipid, phosphatidylserine, is present in the membrane on the outside of viruses, but is sequestered towards the interior of human cells under normal conditions.

The researchers found that the peptoids inactivated all three enveloped viruses – Zika, Rift Valley fever, and chikungunya – by disrupting the virus membrane, but did not disrupt coxsackievirus B3, the only virus without a membrane.

Moreover, chikungunya virus containing higher levels of phosphatidylserine in its membrane was more susceptible to the peptoids. In contrast, a membrane formed exclusively with a different lipid named phosphatidylcholine was not disrupted by the peptoids, suggesting that phosphatidylserine is crucial in order for peptoids to reduce viral activity.

“We’re now starting to understand how peptoids actually exert their antiviral effect—specifically, through the recognition of phosphatidylserine,” said Tate.

Edited by Diana Spencer, Senior Digital Content Editor, Drug Discovery World

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