The Bridge - Issue 1, 2021 - 19

Feature

Researchers Across Oak Ridge National Laboratory Team
to Pursue COVID-19 Treatment Options

Isotope Reactor and the Spallation Neutron Source
at ORNL.
After generating the poses, the team had a lot of data
analysis work left to do. The team calculated features
of the poses to apply different machine-learning
models to reevaluate them and to better determine
whether or not each compound was a strong binder
to the main protease. To analyze the massive amount
of data-1.3 terabytes per large-scale calculation-the
team implemented a " virtual laboratory " on Summit
to sort, manipulate, and join data pieces together.
Results are being validated experimentally by ORNL's
Stephanie Galanie, who is performing test-tube
experiments of the main protease binding to different
compounds (Figure 1). Based on her results, the
researchers are refining their approach and informing
future predictions. They also expect to look at other
proteins in the future-including ones that may be
even better targets for computational approaches.

X-ray study explores potential of
hepatitis C drugs to treat COVID-19
Experiments led by researchers at ORNL have
determined that several hepatitis C drugs can inhibit
the SARS-CoV-2 main protease, a crucial protein
enzyme that enables the novel coronavirus
to reproduce.
Inhibiting, or blocking, this protease from functioning
is vital to stopping the virus from spreading in
patients with COVID-19. The study, published in
the journal Structure, is part of efforts to quickly
develop pharmaceutical treatments for COVID-19 by
repurposing existing drugs known to effectively treat
other viral diseases [1].
" Currently, there are no inhibitors approved by the
Food and Drug Administration that target the SARSCoV-2 main protease, " said ORNL's Daniel Kneller.
" What we found is that hepatitis C drugs bind to and
inhibit the coronavirus protease. This is an important
first step in determining whether these drugs should
be considered as potential repurposing candidates to
treat COVID-19. "
The SARS-CoV-2 coronavirus spreads by expressing
long chains of polyproteins that must be cut by the

THE BRIDGE

main protease to become functional proteins, making
the protease an important drug target for researchers
and drug developers.
In the study, the team looked at several well-known
drug molecules for potential repurposing efforts
including leupeptin, a naturally occurring protease
inhibitor, and three FDA-approved hepatitis C protease
inhibitors: telaprevir, narlaprevir, and boceprevir.
The team performed room temperature X-ray
measurements to build a 3D map that revealed how
the atoms were arranged and where chemical bonds
formed between the protease and the drug
inhibitor molecules.
The experiments yielded promising results for certain
hepatitis C drugs in their ability to bind and inhibit the
SARS-CoV-2 main protease-particularly boceprevir
and narlaprevir. Leupeptin exhibited a low binding
affinity and was ruled out as a viable candidate.
To better understand how well or how tightly the
inhibitors bind to the protease, they used in vitro
enzyme kinetics, a technique that enables researchers
to study the protease and the inhibitor in a test
tube to measure the inhibitor's binding affinity, or
compatibility, with the protease. The higher the
binding affinity, the more effective the inhibitor is at
blocking the protease from functioning.
" What we're doing is laying the molecular foundation
for these potential drug repurposing inhibitors by
revealing their mode of action, " said ORNL's Andrey
Kovalevsky. " We show on a molecular level how they
bind, where they bind, and what they're doing to the
enzyme shape. And, with in vitro kinetics, we also
know how well they bind. Each piece of information
gets us one step closer to realizing how to stop
the virus. "
The study also sheds light on a peculiar behavior
of the protease's ability to change or adapt its shape
according to the size and structure of the inhibitor
molecule it binds to. Pockets within the protease
where a drug molecule would attach are highly
malleable, or flexible, and can either open or close
to an extent depending on the size of the
drug molecules.

Researchers Across Oak Ridge National Laboratory Team
to Pursue COVID-19 Treatment Options

Before the paper was published, the researchers
made their data publicly available to inform and
assist the scientific and medical communities.
More research, including clinical trials, is necessary
to validate the drugs' efficacy and safety as a
COVID-19 treatment.

REFERENCES

" The research suggests that hepatitis C inhibitors
are worth thinking about as potential repurposing
candidates. Immediately releasing our data allows the
scientific community to start looking at the interactions
between these inhibitors and the protease, " said
ORNL's Leighton Coates. " You can't design a drug
without knowing how it works on a molecular
level, and the data we're providing is exactly what
developers need to design stronger, more tightly
binding drugs for more effective treatments. "

FEATURED RESEARCHER

" These experiments have been scaled up to test
hundreds of potential inhibitors at a time, which
allows the researchers to test predictions from
molecular biophysicists and computational chemists
using docking approaches, " said ORNL's Stephanie
Galanie. The structural biologists and medicinal
chemists on the cross national laboratory team are
also designing new molecules based on structural
insights to be assayed.
The research team plans to conduct neutron
scattering experiments to locate the hydrogen
atom positions and the network of chemical bonds
between the protease and the inhibitor molecules.
The paper's co-authors also include Stephanie
Galanie, Gwyndalyn Phillips, and Hugh M. O'Neill.

Feature

[1] D. W. Kneller, S. Galanie, G. Phillips, H. M. O'Neill, L.
Coates, A. Kovalevsky. " Malleability of the SARS-CoV-2 3CL
Mpro active-site cavity facilitates binding of clinical antivirals, "
Structure, vol. 28, pp. 1313-1320, Dec. 2020. doi: https://
doi.org/10.1016/j.str.2020.10.007

Dr. Stephanie Galanie is a
Liane B. Russell fellow in the
Biosciences Division's Metabolomics
and Bioconversion Group at
ORNL. Dr. Galanie is a biological
and analytical chemist interested
in biosynthesis, biocatalysis, and
natural products. She applies highthroughput heterologous microbial expression and mass
spectrometry techniques to probe metabolism and help
answer systems biology questions. Current efforts involve
Populus (poplar tree) enzyme and pathway discovery
for accelerated domestication to reduce recalcitrance to
deconstruction, increase drought tolerance and productivity,
and manipulate metabolic profiles. She earned her Ph.D. in
chemistry at Stanford University, engineering yeast with up to
23 genes to synthesize medicinal natural products and detect
levels of molecules altered by metabolic engineering. She
then joined Codexis, a publicly traded protein engineering
company in the San Francisco Bay area, where she was
responsible for high-throughput biocatalysis and analytical
chemistry, initiated high-throughput mass spectrometry
efforts, and co-led an enzyme-directed evolution program
that resulted in collaborator Tate & Lyle's introduction of
Tasteva® to market.

-Rachel McDowell and Jeremy Rumsey

ACKNOWLEDGMENTS

This research was supported by the DOE Office of
Science through the National Virtual Biotechnology
Laboratory, a consortium of DOE national laboratories
focused on response to COVID-19, with funding
provided by the Coronavirus CARES Act.

HKN.ORG

19


https://www.doi.org/10.1016/j.str.2020.10.007 https://www.doi.org/10.1016/j.str.2020.10.007 https://hkn.ieee.org/ https://hkn.ieee.org/

The Bridge - Issue 1, 2021

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