New antiviral drug combination is highly effective against SARS-CoV-2,
study finds

Date:
February 8, 2022
Source:
University of Pennsylvania School of Medicine
Summary:
Researchers have identified a powerful combination of antivirals
to treat COVID-19. Combining the drug brequniar with remdesivir
or molnupiravir - - both approved by the U.S. Food and Drug
Administration for emergency use -- inhibited the SARS-CoV-2 virus
in human respiratory cells and in mice.



FULL STORY ========================================================================== Researchers have identified a powerful combination of antivirals to treat COVID-19. Combining the drug brequniar with remdesivir or molnupiravir
-- both approved by the U.S. Food and Drug Administration for emergency
use - - inhibited the SARS-CoV-2 virus in human respiratory cells and
in mice, according to a new study led by researchers in the Perelman
School of Medicine at the University of Pennsylvania and the University of Maryland School of Medicine. The findings, published this week in Nature, suggest that these drugs are more potent when used in combination than individually.


========================================================================== Though they have not yet been tested in clinical trials, the combinations
of drugs identified in their study have the potential to become very
promising COVID-19 treatments, says principal investigator Sara Cherry,
PhD, a professor of Pathology and Laboratory Medicine at Penn, who led
the research with David Schultz, PhD, technical director of the Penn High-Throughput Screening Core, and Matthew Frieman, PhD, of the Center
for Pathogen Research at the University of Maryland School of Medicine,
along with collaborators from the National Institutes of Health.

"Identifying combinations of antivirals is really important, not only
because doing so may increase the drugs' potency against the coronavirus,
but combining drugs also reduces the risk of resistance," Cherry said.

SARS-CoV-2, the virus that causes COVID-19, has infected 382 million
people and led to 5 million deaths worldwide. There remains an urgent
need for therapeutics to treat COVID-19, which has been amplified by the emerging threats of new variants that may evade vaccines. In response
to this demand, Cherry and a team of collaborators have screened 18,000
drugs in search of antiviral activity, using live SARS-CoV-2 infection
in human respiratory epithelial cells, because lung cells are the major
target for the virus.

The researchers identified 122 drugs that showed antiviral activity and selectivity against the coronavirus, including 16 nucleoside analogs --
the largest category of antivirals that are used clinically. Among the
16 were remdesivir, which is given by injection into a vein and has been approved by the FDA to treat COVID-19, and molnupiravir, an oral pill
that was authorized for use in December.

Also among the 122 drug candidates, the researchers identified a panel
of host nucleoside biosynthesis inhibitors, including the experimental
drug brequinar.

Nucleoside biosynthesis inhibitors work by blocking the body's own enzymes
from making nucleosides, which prevents the virus from being able to
"steal" RNA building blocks and replicate. Brequinar is currently being
tested in clinical trials as a COVID-19 treatment and as part of a
potential combination therapy for some cancers.



========================================================================== Cherry and collaborators hypothesized that combining brequinar with
a nucleoside analogue, such as remdesivir or molnupiravir, could
work "synergistically" to create a more potent effect against the
virus. Synergistic interactions occur when the total effect of two or
more drugs is greater than the sum of the individual effects of each drug.

"We thought that using these nucleoside analogues while also reducing
the levels of the host's nucleoside building blocks might work together
to super destroy the virus," Cherry said. "It is really amazing that
when you combine them, the virus is completely dead." The researchers
tested the drugs in lung cells as well as in mice, and found that
these combinations were highly effective against multiple strains of
the coronavirus, including the delta variant. The team is now in the
process of testing the drugs against omicron.

Additionally, the researchers found that Paxlovid -- an oral antiviral
that was also recently authorized by the FDA -- could be combined with remdesivir or molnupiravir for an "additive" effect against SARS-CoV-2.

The next step would be for these drug combinations to be tested in
clinical trials.

"As new strains of the virus emerge, the need for new treatments
will remain critical," said Frieman, co-principal investigator of
the study. "We now know that there are a number of powerful drug
combinations that have the potential to alter the trajectory of the
virus." This work was supported by grants from the National Institutes
of Health (R01AI074951, R01AI122749, 1R21AI151882, R01AI140539), as
well as funding from the Penn Center for Precision Medicine, Mercatus,
and the Bill and Melinda Gates Foundation.

========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. David C. Schultz, Robert M. Johnson, Kasirajan Ayyanathan,
Jesse Miller,
Kanupriya Whig, Brinda Kamalia, Mark Dittmar, Stuart Weston,
Holly L.

Hammond, Carly Dillen, Jeremy Ardanuy, Louis Taylor, Jae Seung Lee,
Minghua Li, Emily Lee, Clarissa Shoffler, Christopher Petucci,
Samuel Constant, Marc Ferrer, Christoph A. Thaiss, Matthew
B. Frieman, Sara Cherry. Pyrimidine inhibitors synergize with
nucleoside analogues to block SARS-CoV-2. Nature, 2022; DOI:
10.1038/s41586-022-04482-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220208105308.htm
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