Page 16 - Abacoa Community News - November '22

Page 16, Abacoa
scieNce ON the cUttiNG edGe

The Scripps Research Institute News

New Drug Has Potential the researchers think the drug is likely to be effective against Infectious Diseases announced it is establishing nine

To Turn COVID-19 Virus many other variants of SARS-CoV-2. multi-institution centers focused on developing new

“We expect this compound would continue to be
medications to address the ongoing COVID-19 crisis, and
Against Itself effective even as new variants emerge, because it doesn’t to treat other viruses with pandemic potential. Seven UF
rely on attacking parts of the virus that commonly mutate,” Scripps faculty will contribute to three of those centers.
A n e w dr u g says Chang-ki Oh, a senior staff scientist and first author “UF Scripps is a thriving place to start my research
designed by scientists of the new paper. program,” Burke said. “There is a lot of collaboration,
at Scripps Research Though they have only studied the compound in animal a lot of cross-disciplinary studies, and there are drug
can turn the COVID-19 models, the team is now making a version of the drug to discovery resources you just don’t have most places.”
virus into a harbinger evaluate for human use, while carrying out additional
of its own doom. safety and effectiveness trials in animals. This work is Opioid Drug Tolerance Develops
The drug, NMT5, being sponsored by the Scripps Center Grant for Antiviral
described in Nature Medicines & Pandemic Preparedness (CAMPP AViDD) From Interplay Of Key Gene
Chemical Biology on from the National Institutes of Health (U19 AI171443).
Sept. 29, coats SARS- “These exciting findings suggest a new avenue for And Cholesterol
CoV-2 with chemicals drug development that requires drug combinations for
that can temporarily alter the human ACE2 receptor – the effective pandemic preparedness,” says co-author Arnab UF Scripps Biomedical
molecule the virus normally latches onto to infect cells. Chatterjee, Ph.D Research scientists have
That means that when the virus is near, its path into human discovered a key gene that is
cells via the ACE2 receptor is blocked; in the absence of Biochemist Studying How shedding light on how people
the virus, however, ACE2 can function as usual. Cells Defend Against Viruses develop tolerance to pain
“What’s so neat about this drug is that we’re actually relievers over time, a problem
turning the virus against itself,” says senior author Stuart Joins UF Scripps that raises risk of addiction and
Lipton, M.D., Ph.D., the Step Family Endowed Chair and overdose.
Scripps Research professor. “We’re arming it with little A new scientist joining The finding could open the
molecular warheads that end up preventing it from infecting UF Scripps Biomedical door to a new generation of
our cells; it’s our revenge on the virus.” Research, James M. pain medications designed to
Before the COVID-19 pandemic, Lipton and his Burke, Ph.D., is exploring function differently and lower
colleagues had long been studying variations of the drug how our innate immune the chance patients could grow dependent on opioids and other
memantine, which Lipton developed and patented in the system protects us from drugs like morphine and fentanyl.
1990s for treating neurological diseases like Alzheimer’s. viruses – including the People who suffer severe pain from stroke, trauma or cancer
While memantine originated from an anti-influenza drug pandemic coronavirus – know that over time, the most effective prescription pain relievers
used in the 1960s, clinicians began investigating it for and how viruses evade lose power, said UF Scripps neuroscientist Kirill Martemyanov,
additional diseases after they noticed a woman with these defenses. Ph.D. To provide patients with the same pain-relieving effect,
Parkinson’s symptoms improved when she took the drug Burke says he hopes doctors often must prescribe higher and higher doses.
for the flu. the work will lead to new To date, why this tolerance to opioids develops has not
“My team had made these antiviral drugs better for medicines that thwart James M. Burke, Ph.D., been clearly understood. The new study, led by Martemyanov
the brain, and when COVID-19 emerged, we wondered viruses’ ability to make has joined the molecular at UF Scripps and Brock Grill, Ph.D. at the Seattle Children’s
whether we had also, in the process, made any of them copies of themselves inside medicine department at UF Research Institute and the University of Washington, shows
better antivirals,” says Lipton. our cells. And because our Scripps. He studies how cells a key role for a gene known as PTCHD1, which is involved
Lipton and his team tested a library of compounds cells’ viral defenses can defend themselves from viral in altering cholesterol content in a cell’s membrane.
similar to memantine in overall structure but covered with become inappropriately attack. In addition to offering new directions for pain medication
additional pharmacological warheads. They pinpointed activated and cause other development, the discovery raises the possibility that
the drug candidate designated NMT5 as having two key illnesses, the work may contribute to new approaches cholesterol in the cell membrane may affect how people
properties: It could recognize and attach to a pore on the for treating inflammatory diseases, autoimmune diseases, respond to other drugs, too.
surface of SARS-CoV-2, and it could chemically modify cancer and more. Hundreds of receptors act as landing sites for medications
human ACE2 using a fragment of nitroglycerin as the “We’re pleased to welcome James Burke to our faculty. and biological molecules on the surface of cells. Like a baseball
warhead. The group realized this could turn the virus into His impactful work complements our expertise in the catcher at home plate, mu opioid receptors specifically catch
a delivery vehicle for its own demise. study of viral diseases, autoimmune diseases and RNA morphine or related drug molecules. When they do, systems
In the new paper, Lipton’s group characterized and biology,” said Patrick Griffin, Ph.D., scientific director within the cell responsible for pain relief, slowed breathing
tested NMT5 in isolated cells as well as animals. They and professor of molecular medicine at UF Scripps. “With and even digestive changes become activated. Scientists call
showed how NMT5 attaches tightly to SARS-CoV-2 viral our unique drug-discovery capabilities, and the clinical the group of landing sites GPCRs, short for G-protein coupled
particles as the viruses move through the body. Then, and research strengths of the University of Florida’s receptors. About one-third of all medications act on a GPCR,
they revealed the details of how the drug adds a chemical academic health center, this campus has become a premier making them of great interest to scientists. Finding a gene that
(similar to nitroglycerin) to certain molecules if it gets close research center for up-and-coming scientists to establish drives tolerance to opioids by altering cholesterol in the cell
enough. When the virus gets near ACE2 to infect a cell, their independent programs.” membrane surprised the researchers.
that translates into NMT5 adding a “nitro group” to the When a virus infects a cell, it has one goal: hijack the “There are more than 800 known G-protein coupled
receptor. When ACE2 is modified in this way, its structure cell’s protein-building systems to make new copies of receptors, and regulation of cholesterol by genes in this
temporarily shifts – for about 12 hours – so that the SARS- itself. Multiple immune defense systems work together to family could be important to understanding many of
CoV-2 virus can no longer bind to it to cause infection. interfere with this process. Sorting out how these innate them,” said Martemyanov, who chairs the UF Scripps
“What’s really beautiful is that this only knocks down systems are activated in both a healthy and unhealthy Department of Neuroscience.
availability of ACE2 locally when the virus is coming at manner is important, Burke said. The pandemic revealed Understanding how cholesterol may drive tolerance is an
it,” says Lipton. “It doesn’t knock down all the function of large gaps in scientific knowledge in this area, he added. important advance in the quest to find a new generation of
ACE2 elsewhere in the body, allowing for normal function “I think this pandemic is a wake-up call to start pain medications less prone to causing overdose, he added.
of this protein.” understanding the fundamentals of viral infection and In their quest to better understand opioid tolerance, the team
In cell culture experiments testing how well the Omicron our cells’ response to infection,” Burke said. of scientists chose to conduct an “unbiased” genetic screen
variant of SARS-CoV-2 can attach to human ACE2 Burke joined the molecular medicine department working with a type of tiny worm called C. elegans. Unbiased
receptors, the drug prevented 95 percent of viral binding. at UF Scripps Biomedical Research in Jupiter, Fla., in genetic screens allow the organism’s biology to reveal what’s
In hamsters with COVID-19, NMT5 decreased virus levels June following a postdoctoral fellowship with noted happening, without preconceived ideas of specific genes that
by hundred-fold, eliminated blood vessel damage in the biochemist Roy Parker, Ph.D., an investigator with the might be involved. Researchers often use simpler animal
animals’ lungs, and ameliorated inflammation. The drug also Howard Hughes Medical Institute and the University of models like worms for this purpose.
showed effectiveness against nearly a dozen other variants of Colorado, Boulder. An “unbiased” screen for genes involved in opioid
COVID-19, including alpha, beta, gamma and delta strains. Working with Parker, Burke uncovered the mechanism tolerance relied upon tiny worms called C. elegans. The
Most antiviral drugs work by directly blocking part of a underlying how cells express critical antiviral genes, such worm genetics revealed PTCHD1 plays a key role, altering
virus – which can pressure the virus to evolve resistance to as type I interferons, while simultaneously limiting viral cholesterol in cell membranes.
the drug. Since NMT5 is only using the virus as a carrier, gene expression. He earned his doctorate at the University They started by altering the genome of C. elegans worms
of Texas, Austin with adviser Christopher Sullivan, Ph.D., to add the mammalian mu opioid receptor, to make the worms
where he helped discover how DNA tumor viruses and responsive to pain-relieving drugs. Treating them with fentanyl
retroviruses evade host immune responses. and morphine left the genetically altered worms paralyzed at
Within cells, many different types of RNA do the first, but that effect diminished with repeated exposure, as the
Captain’s was established in 1980 servicing work of reading genes and building the information worms developed tolerance.
Palm Beach County and is a privately they encode. Better understanding their role is critical The genetically altered worms were then subjected to
owned and managed company. to preparing us for the next new viral threat, he said. random genetic changes, silencing various genes. Those that
Captain’s is committed to providing “When viruses are evolving so rapidly, we need as stopped showing tolerance were selected for further testing
dependable, reliable and professional
ground transportation to and from all many tools as we can get,” he said. to see what made them different. One gene that encoded a
South Florida Airports and Seaports. PBCVH212 Multiple scientists at UF Scripps are joining the membrane protein stood out. The closest mammalian version
To reserve your vehicle: $577 million federal effort to develop new antiviral of this gene was PTCHD1.
561-798-2180 or 800-634-7890 www.captainsairport.com drugs to treat the pandemic coronavirus and other viral
threats. Last month the National Institute of Allergy and Scripps Research on page 17