Novel antiviral drug combinations demonstrate COVID-19 therapeutic
potential

Date:
March 7, 2022
Source:
Columbia University School of Engineering and Applied Science
Summary:
Researchers demonstrate that combinations of antiviral drugs
inhibiting both polymerase and exonuclease reduce SARS-CoV-2
replication 10 times more than polymerase inhibitors alone.



FULL STORY ========================================================================== Researchers from Columbia Engineering, Fiocruz's Center for Technological Development in Health and the Oswaldo Cruz Institute in Brazil, Memorial
Sloan Kettering Cancer Center, and Rockefeller University recently
reported that, by combining inhibitors of polymerases and exonucleases
-- enzymes that allow SARS-CoV-2 to reproduce -- they were able to
reduce SARS-CoV-2 replication 10 times more than when using just the
polymerase inhibitors. They also identified a polymerase inhibitor with a unique modification that largely resists its removal from the RNA by the exonuclease. Their findings from both the molecular and cellular levels
reveal the great potential of novel antiviral drug combinations to stop
the spread of COVID-19 and other coronavirus diseases. The study was
published February 22 by Communications Biology, an open access journal
from Nature Portfolio.


========================================================================== "COVID has created an unprecedented public health crisis, with severe
effects on the global economy and infrastructure; however, we can use the
power of science to stop this pandemic," said the Columbia team leader
Jingyue Ju, Samuel Ruben-Peter G. Viele Professor of Engineering;
professor of chemical engineering and pharmacology; and director,
Center for Genome Technology & Biomolecular Engineering. "We expect
drug combinations like the ones we found will powerfully inhibit RNA
viruses such as SARS-CoV-2 and other coronaviruses that could lead to
future pandemics. Because polymerase and exonuclease are highly conserved enzymes in coronaviruses with very rare mutations appearing in variants,
we anticipate that therapeutics developed to target these enzymes
should be widely applicable to all coronaviruses with the potential to
cause serious disease." SARS-CoV-2, the coronavirus causing the global COVID-19 pandemic, uses a protein called polymerase to replicate its
RNA genome inside infected human cells. In theory, terminating the
polymerase reaction should stop the propagation of the coronavirus,
leading to its eradication by the human host's immune system. However, SARS-CoV-2 has two key enzymes that allow it to replicate: the polymerase
which reproduces its RNA and a proofreading exonuclease that corrects
errors in the replication process.

The presence of the exonuclease for proofreading is unique to the
coronaviruses and is needed to reduce the number of mutations and
thereby maintain the integrity and function of the large RNA genomes of coronaviruses. Thus, the vaccine approach has been quite effective in containing the COVID-19 pandemic because the coronaviruses do not mutate
as frequently as influenza virus and HIV, which have no proofreading
function and therefore mutate more frequently.

Nucleotide-based viral polymerase inhibitors are very successful drugs
for treating HIV and hepatitis viruses B and C infections. However,
because of the presence of the proofreading exonuclease in SARS-CoV-2,
which can remove these inhibitors from the RNA, the polymerase inhibitor Remdesivir, the sole FDA- approved drug for COVID-19, is not as effective
as hoped for in preventing serious disease. If the exonuclease could be concurrently inhibited or its activity evaded, viral replication would
be more efficiently blocked.

The research team, led by Ju and Dr. Thiago Souza, Full Researcher at
the Oswaldo Cruz Institute's Center for Technological Development in
Health, decided to investigate whether the combination of polymerase
and exonuclease inhibitors could work together to inhibit replication
of SARS-CoV-2 more effectively, or if polymerase inhibitors with
certain modifications could resist removal by the exonuclease. The
Columbia Engineering team conceived the overall project and performed the molecular-level studies to identify interactions among the inhibitors and enzymes, using a novel mass-spectrometry- based approach. The Brazilian
team designed and conducted the cellular studies to measure the inhibitory effects of drug combinations on virus reproduction.

Dr. Thomas Tuschl's group at Rockefeller University and Dr. Dinshaw
Patel's team at Memorial Sloan Kettering Cancer Center produced the
polymerase and exonuclease complexes used in the molecular studies.

Souza's group demonstrated that the polymerase and exonuclease inhibitors
work together to block the virus's ability to reproduce in infected
lung cells.

"While these results were obtained in a cell culture model, we purposely
chose inhibitors already approved as drugs for treatment of other common
virus infections, such as those caused by HIV and hepatitis viruses,
with the aim of being able to quickly advance them to clinical trials,"
Souza noted.

The team is now exploring whether the enhanced antiviral effects of
the combination drugs can be demonstrated in a COVID-19 animal model,
with acceptable pharmacological properties. If the results are positive,
these drugs can be moved rapidly to clinical trials as they have been previously approved for treatment of other viral infections. They have
also established an initiative with a consortium of pharmacologists, virologists, medicinal chemists, and structural biologists to develop
new therapeutics with enhanced potency and safety profiles for COVID-19
based on the discoveries reported in this study.

========================================================================== Story Source: Materials provided by Columbia_University_School_of_Engineering_and_Applied Science. Original
written by Holly Evarts. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Xuanting Wang, Carolina Q. Sacramento, Steffen Jockusch, Ota'vio
Augusto
Chaves, Chuanjuan Tao, Natalia Fintelman-Rodrigues, Minchen
Chien, Jairo R. Temerozo, Xiaoxu Li, Shiv Kumar, Wei Xie,
Dinshaw J. Patel, Cindy Meyer, Aitor Garzia, Thomas Tuschl,
Patri'cia T. Bozza, James J. Russo, Thiago Moreno L. Souza,
Jingyue Ju. Combination of antiviral drugs inhibits SARS-CoV-2
polymerase and exonuclease and demonstrates COVID-19 therapeutic
potential in viral cell culture. Communications Biology, 2022; 5
(1) DOI: 10.1038/s42003-022-03101-9 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220307113048.htm

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