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.
Peptoids inactivate enveloped viruses by
disrupting their membranes. Credit: David Song/NYU
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 Ph.D. 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.
Source: Novel molecules fight viruses by bursting their bubble-like membranes (phys.org)
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