Researchers develop platform to screen for new class of coronavirus
antiviral compounds

Date:
December 14, 2021
Source:
Johns Hopkins University Bloomberg School of Public Health
Summary:
A new high-throughput platform screens for drug compounds that
hit a target found in human and bat coronaviruses and could be
used to develop future treatments.



FULL STORY ========================================================================== Researchers investigating ways to develop a novel class of antiviral drugs
to treat coronaviruses, including SARS-CoV-2, which causes COVID-19, have developed a platform that can rapidly screen thousands of compounds to
identify potential candidates. The team, led by researchers at the Johns Hopkins Bloomberg School of Public Health, used their new high-throughput platform to screen drug compounds that inhibit the macrodomain --
a protein fold that plays a critical role in the coronavirus life cycle.


========================================================================== Prior studies suggest that some coronaviruses as well as alphaviruses
largely lose their ability to replicate in cells and cause diseases in
animals when their macrodomain's enzymatic activity is disrupted. In this study, researchers targeted the macrodomain of SARS-CoV-2 called Mac1.

This is thought to be the first high-throughput system that can screen
for compounds that block macrodomain activity. In a proof-of-principle demonstration, they used the screening platform to identify existing
drugs that block the coronavirus Mac1 activity. The researchers then
showed that one of these drugs did not disrupt the enzymatic activity
of the human macrodomain that is most similar to Mac1. Compounds that
affect human macrodomains would be more likely to cause unwanted side
effects in patients.

The new screening platform may enable the development of broad-spectrum
drugs that treat existing coronaviruses, including SARS-CoV-2, and
potentially new coronaviruses that could emerge from animal reservoirs
such as bats.

The findings were published December 14 in the journal ACS Chemical
Biology.

"A viral-specific macrodomain inhibitor drug could be very useful in the treatment of COVID-19, MERS, and in a possible future pandemic caused by
a novel coronavirus," says study senior author Anthony K. L. Leung, PhD, associate professor in the Bloomberg School's Department of Biochemistry
and Molecular Biology. "While developing new drugs takes time, our
versatile screening platform gives us hope that we can one day find one."
The researchers note that Mac1 is also a promising drug target because
it is preserved in SARS-CoV-2 variants, including Delta and Omicron.



==========================================================================
Mac1 is found in SARS-CoV-2 on a protein called nsp3 (non-structural
protein 3) and has a type of enzyme activity called ADP-ribosylhydrolase activity.

In the study, Leung and colleagues developed a simple assay called
ADPr-Glo that registers, with luminescence, the degree of enzymatic
activity of a macrodomain. In the presence of compounds that inhibit
the macrodomain, luminescence will be reduced. For this demonstration,
they used the assay to rapidly screen two small libraries of existing
drug compounds -- a total of 3,233 compounds -- for their ability to
inhibit Mac1.

The researchers also measured those Mac1-inhibiting compounds' ability to inhibit human MacroD2, an ADP-ribosylhydrolase enzyme that is the closest
human counterpart to Mac1. MacroD2 mutation or deletion is implicated
in cancer formation and neurological disorders. Since compounds that
affect MacroD2 could cause unwanted side effects in patients, the aim
was to demonstrate that this new method could identify compounds that
inhibit Mac1 without affecting MacroD2.

The experiments uncovered one existing drug, dasatinib, that does inhibit
Mac1 with moderate potency, yet does not measurably inhibit the human
MacroD2.

Notably, it also inhibits Mac1 from another highly-pathogenic coronavirus
that causes Middle East Respiratory Syndrome (MERS). Dasatinib is a
leukemia drug that was developed to target another class of enzymes and
thus hits other targets in humans beyond Mac1. Dasatinib is known to be
toxic to cells at the concentrations that inhibited Mac1. It would need modification to become an antiviral against coronavirus infections.

Identifying this drug demonstrates that viral Mac1's unique structure
can be targeted by small-molecule drugs without affecting their closest
human counterpart.



==========================================================================
The ongoing pandemic has renewed urgency around identifying and developing antiviral treatments in the near term and for future pandemics. Earlier
this year, the U.S. National Institute of Allergy and Infectious Diseases launched an Antiviral Program for Pandemics to promote the development
of new drugs to combat viruses with pandemic potential.

The researchers plan to continue screening compounds to identify new
Mac1 inhibitors.

Study senior authors include Huijun Wei, PhD, director of Biochemistry
and Assay Development at Johns Hopkins Drug Discovery at Johns Hopkins University School of Medicine; and structural biologist Ju"rgen Bosch,
PhD, CEO of InterRayBio, LLC, a structure-based drug design company.

"High-throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2
Mac1 Macrodomain" was co-authored by Morgan Dasovich, Junlin Zhuo, Jack Goodman, Ajit Thomas, Robert Lyle McPherson, Aravinth Kumar Jayabalan,
Veronica Busa, Shang-Jung Cheng, Brennan Murphy, Karli Redinger, Yousef Alhammad, Anthony Fehr, Takashi Tsukamoto, Barbara Slusher, Ju"rgen Bosch, Huijun Wei, and Anthony Leung.

The research was supported by the COVID-19 PreClinical Research Discovery
Fund from Johns Hopkins University and Johns Hopkins Bloomberg School
of Public Health Development Fund.

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


========================================================================== Journal Reference:
1. Morgan Dasovich, Junlin Zhuo, Jack A. Goodman, Ajit Thomas,
Robert Lyle
McPherson, Aravinth Kumar Jayabalan, Veronica F. Busa, Shang-Jung
Cheng, Brennan A. Murphy, Karli R. Redinger, Yousef M. O. Alhammad,
Anthony R.

Fehr, Takashi Tsukamoto, Barbara S. Slusher, Ju"rgen Bosch,
Huijun Wei, Anthony K. L. Leung. High-Throughput Activity Assay
for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain. ACS
Chemical Biology, 2021; DOI: 10.1021/acschembio.1c00721 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211214104028.htm

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