Nicos Petasis
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Resolving Inflammation
Inspired by nature, USC College
chemist Nicos Petasis synthesizes compounds that help shed light on
inflammation and offer a new approach to halting its damaging effects.
By Eva Emerson
August 2004
Even the tiniest paper cut kicks the immune system into action.
Infection-fighting white blood cells, called neutrophils, rush to the
site of injury and initiate inflammation.
Calling for back up, the neutrophils quickly recruit more of their
kind to the scene, and commence to kill any bacteria they find. The
skirmishes and casualties cause the skin around the cut to swell and
redden until, victory in sight, the first wave of inflammation
subsides. As the neutrophils retreat, the healing can begin.
Yet, these defensive forces have a dark side as well. Unchecked,
raging inflammation can damage the very tissue the immune system is
designed to protect. In fact, researchers have linked out-of-control
inflammation to an ever-growing list of diseases, from clogged arteries
and heart attacks to arthritis and cancer.
Over the last decade, USC College chemist Nicos A. Petasis has
worked as part of a multi-disciplinary team studying the natural course
of inflammation and what goes wrong in disease. Led by Harvard
biologist Charles N. Serhan, the team’s research has altered
fundamental ideas about the inflammatory response and revealed the role
of biological molecules called lipoxins in regulating the process.
As part of the effort, Petasis and his group synthesized a number of
powerful chemical compounds that mimic lipoxin’s anti-inflammatory,
pro-healing activity. The compounds, called lipoxin analogs, are now
being eyed as candidates for drug development, having shown great
promise in quelling disease-associated inflammation in animal studies
of dermatitis, asthma, and kidney disease.
In recent months, Petasis, a professor of chemistry, has co-authored
reports demonstrating the potential value of the lipoxin analogs as new
therapies in cystic fibrosis and gum disease.
Natural Inspiration
In his efforts to invent new materials and pharmaceuticals, Petasis,
the Harold and Lillian Moulton Chair in Chemistry and member of the
Loker Hydrocarbon Research Institute, looks to nature for inspiration.
Growing up on the island of Cyprus in the Mediterranean, Petasis was
drawn to nature and using science as a tool to explore it early in
life. In high school, he founded a chemistry club, and still fondly
recalls doing his first experiments in the club’s lab. In college in
Greece, Petasis was drawn to the field of organic synthetic chemistry
because of its mixture of logic, creativity and relevance to the
everyday world.
“Synthesis is where the action is, it’s at the heart of chemistry,”
he says. He describes creating molecules from scratch, some that “no
one has ever seen before, completely new,” as both intellectually
challenging and incredibly fulfilling.
During his career, Petasis has built a stellar reputation in the
world of synthetic chemistry, and is especially well known for
developing improved tools and methods that have been adopted in
academic labs and industrial manufacturing.
A Scientific Challenge
Finding ways to improve on nature’s designs was at the heart of the
challenge when Serhan and Petasis began collaborating in 1993.
Serhan and Petasis had worked together earlier as members of their
mentor’s teams — Nobel-prize winning Swedish biologist Bengt Samuelsson
and preeminent synthetic chemist K. C. Nicolaou, respectively — who had
joined forces to study leukotrienes, molecules that turn on the
inflammation cascade.
Although Serhan discovered the lipoxins with Samuelsson in the
1980s, he wasn’t able to fully determine their function for years. A
breakthrough came when he showed why lipoxins had resisted study. They
circulated only a few minutes before enzymes broke them down.
“When Serhan discovered that, we started work synthesizing
longer-lasting lipoxin-like molecules,” Petasis says. “My task was to
protect the molecules from the enzymes without altering their
biological activity.” It was a tricky prospect.
Petasis first conceptualized the kinds of chemical changes that
might protect the molecule. With a rough design in mind, Petasis began
his hands-on work. He would send his most promising molecules to Serhan
to test for activity and metabolic stability. Going through a number of
these loops, he created a few dozen promising analogs. Adding a
fluorine atom to his best prospect, Petasis came up with what he was
after — a potent lipoxin analog that lasts for hours.
Healing Molecules
Using the lipoxin analogs as tools, the team went on to reveal lipoxins
worked as the immune system’s “traffic cops” to halt inflammation,
among other key activities. Anti-inflammatory lipoxins, produced by
neutrophils in the same biochemical cascade that initiates
inflammation, signal other cells to retreat from an inflamed site and
to begin the healing process.
The team’s research also led to a clearer understanding of how
aspirin dampens inflammation. Scientists had known that aspirin works
by blocking pro-inflammatory molecules, but Serhan was the first to
show that aspirin also triggers the formation of a distinct,
longer-lived form of lipoxin, which was first synthesized by Petasis.
The team has gone on to show that lipoxins also promote the clean up of
dead bacteria and cells, and trigger a transition to the less toxic
chronic inflammation.
Promise for Periodontitis
As part of an NIH-funded Program Project, Petasis and dental biologist
Thomas Van Dyke of Boston University joined Serhan and his team at
Brigham and Women’s Hospital and Harvard Medical School to study the
role of lipoxins in periodontal disease.
In December 2003, this group published a report showing lipoxin
analogs helped protect gums and teeth in an animal model of
periodontitis. Rabbits treated topically with the analogs had
significantly less gum inflammation as well as less tissue and bone
loss than an untreated group. These findings suggest that lipoxin
analogs may prove helpful as a therapy for gum disease, the primary
cause of adult tooth loss in the U.S.
A New View of Cystic Fibrosis
In the April 2004 issue of Nature Immunology, Petasis and a team led by
physician-scientist Christopher L. Karp of Cincinnati Children’s
Hospital, found that cystic fibrosis patients produce markedly lower
levels of natural lipoxins than healthy people. The findings are the
strongest evidence to date that uncontrolled inflammation, and not
bacterial infection, initiates the destructive cycle in the lungs that
eventually proves fatal for most sufferers of this genetic disease.
“People have thought of the bacteria as the main cause of lung
damage in CF patients,” says Petasis. “But our results suggest that an
overactive inflammatory response, which fails to resolve, may be the
main culprit.”
The team also tested lipoxin analogs in an animal model of the
disease. The airways of animals treated with the analogs showed less
inflammation, fewer neutrophils and more successful clearing of
bacterial infection than the airways of those receiving no treatment.
Critically, those in the treatment group suffered less overall lung
damage.
Scientists are targeting other diseases as well. In an earlier
project done in collaboration with biomedical scientists, Petasis
showed that lipoxin analogs may also be effective in kidney disease.
Serhan’s group has published extensively on the potential of enhancing
levels of natural lipoxins or using lipoxin analogs to prevent the
build up of dangerous plaques in the arteries.
Petasis has developed a number of second-generation analogs that he
has refined to improve their “shelf-life” or chemical stability. His
first analogs were vulnerable to heat, humidity and other environmental
factors, which made them harder to handle in experiments.
Future Directions
Petasis predicts that unraveling the whole story of inflammation — a tale both complex and redundant — will take time.
“Among many other issues, we still don’t know all of the mechanisms
lipoxins and similar molecules use to halt inflammation, nor how they
interact with other molecules in the pathway,” he says.
But some benefits from the research may arrive sooner.
If the results of animal studies are borne out in future human
trials, Petasis’ pro-healing compounds may offer doctors a potent and
unique new tool in the anti-inflammatory arsenal.
And that, Petasis says, would make a great ending to any story of
chemical synthesis. “I tend to follow-up with what happens with the
molecules I create,” Petasis says. “You care about them as if they were
your offspring. If a molecule you create proves useful, you can have an
enormous positive impact.”
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