Novel molecules fight viruses by bursting their bubble-like membranes
Targeting the membrane of a virus, rather than its proteins, could lead to a new generation of antivirals
VIDEO: PEPTOIDS INACTIVATE ENVELOPED VIRUSES BY DISRUPTING THEIR MEMBRANES. view more
CREDIT: DAVID SONG/NYU
Antiviral therapies are notoriously difficult to develop, as viruses can quickly mutate to become resistant to drugs. But what if a new generation of antivirals ignores the fast-mutating proteins on the surface of viruses and instead disrupts their protective layers?
“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 NYU and the study’s senior author.
In a new study published Aug. 2 in the journal ACS Infectious Diseases, the researchers show how a group of novel molecules inspired by our own immune system inactivates several viruses, including Zika and chikungunya. Their approach may not only lead to drugs that can be used against many viruses, but could also help overcome antiviral resistance.
The urgent need for new antivirals
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. These limitations were on display when new SARS-CoV-2 variants emerged that evaded both the drugs and the vaccines developed against the original virus.
“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,” added Kirshenbaum.
Drawing inspiration from our immune systems
Our innate immune system combats pathogens by producing antimicrobial peptides, the body’s first line of defense against bacteria, fungi, and viruses. 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 synthesized in the lab, they are rarely used to treat infectious diseases in humans because 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.
“We began to think about how to mimic natural peptides and create molecules with many of the same structural and functional features as peptides, but are composed of something that our bodies won't be able to rapidly degrade,” said Kirshenbaum.
The researchers investigated seven peptoids, many originally discovered in the lab of Annelise Barron at Stanford, a co-author of the study. The NYU team studied the antiviral effects of the 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.
How peptoids disrupt viral membranes and avoid other cells
The membranes surrounding viruses are made of different molecules than the virus itself, as 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.
“Because phosphatidylserine is found on the exterior of viruses, it can be a specific target for peptoids to recognize viruses, but not recognize—and therefore spare—our own cells,” said Tate. “Moreover, because viruses acquire lipids from the host rather than encoding from their own genomes, they have better potential to avoid antiviral resistance.”
The researchers tested seven peptoids against the four viruses. They 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.
The researchers are continuing pre-clinical studies to evaluate the potential of these molecules in fighting viruses and to understand if they can overcome the development of resistance. Their peptoid-focused approach may hold promise for treating a wide range of viruses with membranes that can be difficult to treat, including Ebola, SARS-CoV-2, and herpes.
In addition to Kirshenbaum, Tate, and Barron, study authors include Vincent Mastrodomenico, Christina Cunha, and Bryan C. Mounce of Loyola University Chicago Medical Center; Joshua McClure of Maxwell Biosciences; and Gill Diamond of the University of Louisville School of Dentistry.
The research was supported in part by the National Science Foundation (CHE-2002890 and NSF GRFP) and the National Institutes of Health (R35GM138199 and 1DP1 OD029517-01). Kirshenbaum is the Chief Scientific Officer for Maxwell Biosciences, a biotech company that has licensed patents originating from his lab at NYU. The company is seeking to commercialize these compounds and bring them to the clinic to advance human health.
JOURNAL
ACS Infectious Diseases
SUBJECT OF RESEARCH
Cells
ARTICLE PUBLICATION DATE
2-Aug-2023
Mimicking the body’s own defenses to destroy enveloped viruses
Just as bacteria can develop antibiotic resistance, viruses can also evade drug treatments. Developing therapies against these microbes is difficult because viruses often mutate or hide themselves within cells. But by mimicking the way the immune system naturally deals with invaders, researchers reporting in ACS Infectious Diseases have developed a “peptoid” antiviral therapy that effectively inactivates three viruses in lab tests. The approach disrupts the microbes by targeting certain lipids in their membranes.
Viruses are almost like biological “zombies.” They are not quite living or nonliving, and are only able to multiply within a host, such as our body’s cells. Oftentimes, the immune system naturally destroys the pathogens with special molecules such as antibodies.
Less-well-known members of the immune system’s defense force are small protein-like molecules called antimicrobial peptides. These peptides aren’t good drug candidates, though, as they’re expensive to make, are quickly eliminated from the body and can cause side effects. Instead, some researchers have mimicked their function with lab-made molecules called peptoids that aren’t easily degraded by the body and are more economical to produce. Previously, Annelise Barron’s team showed that certain peptoids could pierce and destroy the SARS-CoV-2 and herpes viruses. This time, joined by Kent Kirshenbaum and colleagues, the group wanted to see if the peptoids could inactivate three other “enveloped” viruses enclosed within membranes — Zika, Rift Valley fever and chikungunya virus — as well as one that lacks a membrane envelope, coxsackie B3. No treatments currently exist for infections caused by these microbes.
The peptoids used in these experiments included three of the linear peptoids previously studied by Barron’s team, as well as four new circularized versions with increased antiviral activity. The researchers created model virus membranes using common lipids, including phosphatidylserine (PS). Membranes were disrupted most effectively when PS was present in higher concentrations, suggesting that the peptoids target it specifically. Though both human and viral membranes contain the lipid, it’s distributed differently in each instance, allowing an antiviral to preferentially attack the invader instead of the host. Next, the team incubated the peptoids with whole, infectious virus particles. Again, each worked to a different extent on the three enveloped viruses: some disrupted all three, some only one. However, none of the peptoids could inactivate the non-enveloped coxsackie B3 virus, showing that the mechanism of action hinges on the presence of the viral envelope. The team says that understanding this mechanism could inform the design of future peptoid-based antiviral treatments, and could be used to create drugs already armed against the next emerging viral threat.
The authors acknowledge funding from the National Science Foundation, the National Institutes of Health, Stanford University’s Discovery Innovation Fund, the Cisco University Research Program Fund, the Silicon Valley Community Foundation, and Dr. James Truchard and the Truchard Foundation. Kirshenbaum is the Chief Scientific Officer for and has material financial interests in Maxwell Biosciences, which is working to commercialize peptoid oligomers as anti-infective agents.
The paper’s abstract will be available on Aug. 2 at 8 a.m. Eastern time here: http://pubs.acs.org/doi/abs/10.1021/acsinfecdis.3c00063
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JOURNAL
ACS Infectious Diseases
ARTICLE TITLE
Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity
ARTICLE PUBLICATION DATE
2-Aug-2023
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