Compounds halt SARS-CoV-2 replication by targeting key viral enzyme
Four promising antiviral drug candidates identified and analyzed in preclinical study

Date:
July 6, 2020
Source:
University of South Florida (USF Health)
Summary:
New research identifies several existing compounds that block
replication of the COVID-19 virus (SARS-CoV-2) within human cells
grown in the laboratory. The inhibitors all demonstrated potent
chemical and structural interactions with a viral protein critical
to the virus's ability to proliferate.



FULL STORY ========================================================================== [SARS-CoV-2 virus | Credit: (c) Kateryna_Kon / stock.adobe.com] SARS-CoV-2 virus illustration (stock image).

Credit: (c) Kateryna_Kon / stock.adobe.com [SARS-CoV-2 virus | Credit:
(c) Kateryna_Kon / stock.adobe.com] SARS-CoV-2 virus illustration
(stock image).

Credit: (c) Kateryna_Kon / stock.adobe.com Close As the death toll from
the COVID-19 pandemic mounts, scientists worldwide continue their push
to develop effective treatments and a vaccine for the highly contagious respiratory virus.


========================================================================== University of South Florida Health (USF Health) Morsani College of
Medicine scientists recently worked with colleagues at the University
of Arizona College of Pharmacy to identify several existing compounds
that block replication of the COVID-19 virus (SARS-CoV-2) within human
cells grown in the laboratory. The inhibitors all demonstrated potent
chemical and structural interactions with a viral protein critical to
the virus's ability to proliferate.

The research team's drug discovery study appeared June 15 in Cell
Research, a high-impact Naturejournal.

The most promising drug candidates -- including the FDA-approved
hepatitis C medication boceprevir and an investigational veterinary
antiviral drug known as GC-376 -- target the SARS-CoV-2 main protease
(Mpro), an enzyme that cuts out proteins from a long strand that the
virus produces when it invades a human cell. Without Mpro, the virus
cannot replicate and infect new cells. This enzyme had already been
validated as an antiviral drug target for the original SARS and MERS,
both genetically similar to SARS-CoV-2.

"With a rapidly emerging infectious disease like COVID-19, we don't have
time to develop new antiviral drugs from scratch," said Yu Chen, PhD,
USF Health associate professor of molecular medicine and a coauthor of
the Cell Research paper. "A lot of good drug candidates are already out
there as a starting point. But, with new information from studies like
ours and current technology, we can help design even better (repurposed)
drugs much faster." Before the pandemic, Dr. Chen applied his expertise
in structure-based drug design to help develop inhibitors (drug compounds)
that target bacterial enzymes causing resistance to certain commonly
prescribed antibiotics such as penicillin. Now his laboratory focuses
its advanced techniques, including X-ray crystallography and molecular
docking, on looking for ways to stop SARS-CoV-2.



==========================================================================
Mpro represents an attractive target for drug development against
COVID-19 because of the enzyme's essential role in the life cycle of the coronavirus and the absence of a similar protease in humans, Dr. Chen
said. Since people do not have the enzyme, drugs targeting this protein
are less likely to cause side effects, he explained.

The four leading drug candidates identified by the University of
Arizona-USF Health team as the best (most potent and specific) for
fighting COVID-19 are described below. These inhibitors rose to the top
after screening more than 50 existing protease compounds for potential repurposing:
* Boceprevir, a drug to treat Hepatitis C, is the only one of the four
compounds already approved by the FDA. Its effective dose,
safety profile, formulation and how the body processes the drug
(pharmacokinetics) are already known, which would greatly speed up
the steps needed to get boceprevir to clinical trials for COVID-19,
Dr. Chen said.

* GC-376, an investigational veterinary drug for a deadly strain of
coronavirus in cats, which causes feline infectious
peritonitis. This agent was the most potent inhibitor of the Mpro
enzyme in biochemical tests, Dr. Chen said, but before human
trials could begin it would need to be tested in animal models
of SARS-CoV-2. Dr. Chen and his doctoral student Michael Sacco
determined the X-ray crystal structure of GC-376 bound by Mpro,
and characterized molecular interactions between the compound and
viral enzyme using 3D computer modeling.

* Calpain inhibitors II and XII, cysteine inhibitors investigated
in the
past for cancer, neurodegenerative diseases and other conditions,
also showed strong antiviral activity. Their ability to dually
inhibit both Mpro and calpain/cathepsin protease suggests these
compounds may include the added benefit of suppressing drug
resistance, the researchers report.

All four compounds were superior to other Mpro inhibitors previously
identified as suitable to clinically evaluate for treating SARS-CoV-2,
Dr. Chen said.

A promising drug candidate -- one that kills or impairs the virus without destroying healthy cells -- fits snugly, into the unique shape of viral
protein receptor's "binding pocket." GC-376 worked particularly well at conforming to (complementing) the shape of targeted Mpro enzyme binding
sites, Dr. Chen said.

Using a lock (binding pocket, or receptor) and key (drug) analogy,
"GC-376 was by far the key with the best, or tightest, fit," he
added. "Our modeling shows how the inhibitor can mimic the original
peptide substrate when it binds to the active site on the surface of the SARS-CoV-2 main protease." Instead of promoting the activity of viral
enzyme, like the substrate normally does, the inhibitor significantly
decreases the activity of the enzyme that helps SARS-CoV-2 make copies
of itself.

Visualizing 3-D interactions between the antiviral compounds and the
viral protein provides a clearer understanding of how the Mpro complex
works and, in the long-term, can lead to the design of new COVID-19
drugs, Dr. Chen said. In the meantime, he added, researchers focus on
getting targeted antiviral treatments to the frontlines more quickly by tweaking existing coronavirus drug candidates to improve their stability
and performance.

Dr. Chen worked with lead investigator Jun Wang, PhD, UA assistant
professor of pharmacology and toxicology, on the study. The work was
supported in part by grants from the National Institutes of Health.


========================================================================== Story Source: Materials provided by
University_of_South_Florida_(USF_Health). Original written by Anne
DeLotto Baier. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Chunlong Ma, Michael Dominic Sacco, Brett Hurst, Julia Alma
Townsend,
Yanmei Hu, Tommy Szeto, Xiujun Zhang, Bart Tarbet, Michael Thomas
Marty, Yu Chen, Jun Wang. Boceprevir, GC-376, and calpain inhibitors
II, XII inhibit SARS-CoV-2 viral replication by targeting the viral
main protease. Cell Research, 2020; DOI: 10.1038/s41422-020-0356-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200706140830.htm

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