News
Treating COVID-19: Bond LSC lab explores effectiveness of remdesivir and other potential drugs
By Jerry Duggan | Bond LSC
As countries hang their hopes on the drug remdesivir for battling
COVID-19, recent modeling and computer-aided drug evaluation at the University
of Missouri caution to keep an open mind to other drug treatments.
Kamlendra
Singh at MU’s Bond Life Sciences Center assessed remdesivir and several other
drugs for long-term success in treating coronavirus causing the pandemic across
the world. His results were published April 26 in the journal Pathogens.
“Remdesivir
is working against COVID-19, but these other drugs are in no way inferior to
it,” said Singh, the assistant director of the MU Molecular Interactions Core,
Bond LSC investigator and MU associate research professor of Molecular
Microbiology and Immunology in the School of Medicine. “They are all FDA
approved and we believe, based on our research, that they are worth looking
into as a form of treatment.
Working
with colleagues at the Karolinska Institutet in Stockholm, Sweden, where he has
an appointment, Singh and his team started their COVID-19 specific research in
earnest on February 20. Through a combination of bioinformatics, molecular
modeling and computer-aided drug design, they evaluated antiviral medicines
remdesivir, favipiravir, 5-Fluorouracil and ribavirin for their effectiveness against
COVID-19, and possible resistance under pressure of these compounds.
While
Singh agrees that remdesivir works against COVID-19, he sees potential
weaknesses of the drug and believes alternatives could supplement its use.
The
team first assessed at the Gilead pharmaceutical remdesivir to inhibit
SARS-CoV-2 viral polymerase, an antiviral drug originally used to treat Ebola.
Remdesivir is one of the most highly touted drugs at this point in the fight
against COVID-19. But Singh’s findings indicate SARS-CoV-2, — the causative
agent of COVID-19 — is capable of mutating — that is, developing alterations in
its genome — that could help it develop resistance to the drug.
Armed
with this conclusion, Singh’s team looked at three additional compounds to
treat the virus. With T-705, also known as favipiravir, they concluded COVID-19
could also develop resistance, but its past effectiveness as a broad-spectrum
inhibitor of RNA viruses made it worth a look as a potential option to treat
COVID-19. Favipiravir, which has been approved in Japan as an anti-influenza
drug, was recently approved in Italy and China for treatment of COVID-19.
Favipiravir is currently undergoing testing regarding its viability against
COVID-19 and results are pending.
Additionally,
Singh’s lab conducted research on two other broad-spectrum RNA polymerase
inhibitors: 5-Fluorouracil and ribavirin. Singh examined 5-Fluorouracil because
RNA polymerase (the enzyme that copies the virus genome) from SARS-CoV-2 is
structurally similar to the RNA polymerases from human Rhinovirus and
Foot-and-Mouth disease viruses and 5-FU shows effectiveness against these
viruses. Due to this structural similarity, it stood to reason that
5-Fluorouracil may also have some effectiveness in treating COVID-19.
Ribavirin
— one of the most widely used, broad spectrum inhibitors of RNA-viruses — shows
unique properties that make it a prime candidate to bind to the active site of
COVID-19. By binding to the active site, ribavirin theoretically could stop the
replication of the viral genome and slow the spread of COVID-19 within an
individual’s body. Still, doubt remains regarding its effectiveness since the
virus can likely develop resistance to ribavirin through mutations or other
mechanisms.
Singh
has been working on coronaviruses — a broader category of viruses of which
COVID-19 is just one specific manifestation — since his arrival at MU in 2009,
so he is no stranger to this area of research. His broad goal is to ultimately
have his research discoveries “make a difference in the lives of patients.”
He
started his work on COVID-19 with the same goal in mind.
“I
did not start my research on COVID-19 in order to write this paper and have it
published,” he said. “I just wanted to do my part and spend some time
researching compounds that could potentially be effective against COVID-19.”
As
detailed as Singh’s findings are, he is quick to acknowledge that he is part of
a global scientific community and had a team of professionals within his lab,
especially Dr. Kyle Hill (a postdoctoral associate) that helped him to complete
this work.
“This
progress is not made by individuals, but by teams,” he said. “I have a talented
group of individuals working with me and collaborating with me. I am well aware
of their expertise and I know how to
best utilize their skills.”
Ujjwal
Neogi, who works at Karolinska Institutet, spearheaded the bioinformatics
portion of the research. Ujjwal also helped in conceptualizing the idea of
exploring already existing drugs to treat COVID-19. This work involved
analyzing genetic code of the viruses, binding of the drugs with the target,
and analyzing sequences of DNA, RNA, or protein to identify regions of
similarity to find the most unchanging, widespread target for using a drug. This
is important work since the smallest of differences in nucleotide sequence can
result in mutations that would render these proposed COVID-19 treatments
ineffective. Neogi was assisted with these tasks by Kyle Hill at the Bond LSC.
Anoop
Ambikan (at Karolinska Institute) used R, a statistical computing and graphics
program, to help put together the models and graphics behind this research.
Xiao Heng, a member of the faculty at MU, used her expertise in biochemistry to
help Singh conceptualize the research trajectory. Thomas Quinn, director of MU’s
Molecular Interactions Core in the Bond LSC, helped with editing and advising
throughout the process. Siddappa Byrareddy (University of Nebraska Medical
Center, Omaha, Nebraska) brought previous experience with the topic of treating
SARS, a form of coronavirus. Anders Sönnerborg, Singh’s longtime collaborator
at Karolinska, provided funding for this work and is the one who takes the
drugs to the clinic if they demonstrate potential. His involvement was important
from the start of the process. Stefan Sarafianos, a former Bond LSC
investigator and current collaborator had engaged with Singh in similar viral
research in the past, and he imparted a lot of knowledge to Singh that enabled
this research.
Taking
a deeper look at potential drugs in an analytical way like this contributes to the
University of Missouri System’s NextGen Precision Health Initiative. The
NextGen Initiative aims to improve large-scale interdisciplinary collaboration
in pursuit of life-changing precision health advancements and research.
While
Singh concedes that none of his team’s work constitutes a guaranteed effective
form of treatment against the virus, he feels that researchers have an
obligation to continue working on a cure, and should not accept the status quo
of hundreds of thousands of deaths globally. He also makes clear that for now
this is all dry lab work. But plans are already in place to test these drugs in
the wet lab for the validation once the appropriate protocols are
established. Funding from the Karolinska
Institute and the submission of two recent COVID related VA grant applications
with Drs. Deutscher and Whaley-Connell will support compound validation and
additional novel compound discovery and characterization.
“These
treatments, if they turn out to be effective, all have limitations,” he
admitted. “But, in the midst of a global pandemic, they are worth taking a
deeper look at, because we have reason to believe, based on our research, that
all of these drugs could potentially be effective in treating COVID-19.”
Kamlendra
Singh is Assistant Director of the MU Molecular Interactions Core and an MU
Associate Research Professor of Veterinary Pathology in the Collage of Veterinary Medicine (as of
May 1, 2020).
Read
more details about this research in “Feasibility
of Known RNA Polymerase Inhibitors as Anti-SARS-CoV-2 Drugs,” published
April 26 in the journal Pathogens.