Breaking COVID-19's 'clutch' to stop its spread
Researchers engineer RNA-targeting compounds that disable the pandemic coronavirus' replication engine

Date:
September 30, 2020
Source:
Scripps Research Institute
Summary:
The virus that causes COVID-19 uses a clutch-like shifter to enable
transcription of one RNA string into multiple proteins, and therein
lies a vulnerability. A proof-of-concept study shows it's possible
to eliminate that shifter with an RNA-binding compound linked to a
'trash this' signal.



FULL STORY ========================================================================== Scripps Research chemist Matthew Disney, PhD, and colleagues have created
drug- like compounds that, in human cell studies, bind and destroy the
pandemic coronavirus' so-called "frameshifting element" to stop the
virus from replicating. The frameshifter is a clutch-like device the
virus needs to generate new copies of itself after infecting cells.


==========================================================================
"Our concept was to develop lead medicines capable of breaking COVID-19's clutch," Disney says. "It doesn't allow the shifting of gears." Viruses
spread by entering cells and then using the cells' protein-building
machinery to churn out new infectious copies. Their genetic material
must be compact and efficient to make it into the cells.

The pandemic coronavirus stays small by having one string of genetic
material encode multiple proteins needed to assemble new virus. A
clutch-like frameshifting element forces the cells' protein-building
engines, called ribosomes, to pause, slip to a different gear, or reading frame, and then restart protein assembly anew, thus producing different
protein from the same sequence.

But making a medicine able to stop the process is far from simple. The
virus that causes COVID-19 encodes its genetic sequence in RNA, chemical
cousin of DNA. It has historically been very difficult to bind RNA with
orally administered medicines, but Disney's group has been developing
and refining tools to do so over more than a decade.

The scientists' report, titled "Targeting the SARS-CoV-2 RNA Genome
with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders," appears Sept. 30 in the journal ACS Central Science.



========================================================================== Disney emphasizes this is a first step in a long process of refinement
and research that lies ahead. Even so, the results demonstrate the
feasibility of directly targeting viral RNA with small-molecule drugs,
Disney says. Their study suggests other RNA viral diseases may eventually
be treated through this strategy, he adds.

"This is a proof-of-concept study," Disney says. "We put the frameshifting element into cells and showed that our compound binds the element and
degrades it. The next step will be to do this with the whole COVID virus,
and then optimize the compound." Disney's team collaborated with Iowa
State University Assistant Professor Walter Moss, PhD, to analyze and
predict the structure of molecules encoded by the viral genome, in search
of its vulnerabilities.

"By coupling our predictive modeling approaches to the tools and
technologies developed in the Disney lab, we can rapidly discover
druggable elements in RNA," Moss says. "We're using these tools not only
to accelerate progress toward treatments for COVID-19, but a host of other diseases, as well." The scientists zeroed in on the virus' frameshifting element, in part, because it features a stable hairpin-shaped segment,
one that acts like a joystick to control protein-building. Binding the
joystick with a drug-like compound should disable its ability to control frameshifting, they predicted. The virus needs all of its proteins to
make complete copies, so disturbing the shifter and distorting even one
of the proteins should, in theory, stop the virus altogether.



========================================================================== Using a database of RNA-binding chemical entities developed by Disney,
they found 26 candidate compounds. Further testing with different variants
of the frameshifting structure revealed three candidates that bound them
all well, Disney says.

Disney's team in Jupiter, Florida quickly set about testing the compounds
in human cells carrying COVID-19's frameshifting element. Those tests
revealed that one, C5, had the most pronounced effect, in a dose-dependent manner, and did not bind unintended RNA.

They then went further, engineering the C5 compound to carry an RNA
editing signal that causes the cell to specifically destroy the viral
RNA. With the addition of the RNA editor, "these compounds are designed
to basically remove the virus," Disney says.

Cells need RNA to read DNA and build proteins. Cells have natural process
to rid cells of RNA after they are done using them. Disney has chemically harnessed this waste-disposal system to chew up COVID-19 RNA. His system
is called RIBOTAC, short for "Ribonuclease Targeting Chimera." Adding a RIBOTAC to the C5 anti-COVID compound increases its potency by tenfold,
Disney says. Much more work lies ahead for this to become a medicine
that makes it to clinical trials. Because it's a totally new way of
attacking a virus, there remains much to learn, he says.

"We wanted to publish it as soon as possible to show the scientific
community that the COVID RNA genome is a druggable target. We have
encountered many skeptics who thought one cannot target any RNA with
a small molecule," Disney says. "This is another example that we hope
puts RNA at the forefront of modern medicinal science as a drug target."

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


========================================================================== Related Multimedia:
* YouTube_video:_Breaking_COVID-19's_'clutch'_to_stop_its_spread ========================================================================== Journal Reference:
1. Hafeez S. Haniff, Yuquan Tong, Xiaohui Liu, Jonathan L. Chen,
Blessy M.

Suresh, Ryan J. Andrews, Jake M. Peterson, Collin A. O'Leary,
Raphael I.

Benhamou, Walter N. Moss, Matthew D. Disney. Targeting the
SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease
Targeting Chimera (RIBOTAC) Degraders. ACS Central Science, 2020;
DOI: 10.1021/ acscentsci.0c00984 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200930085151.htm

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