April 26, 2007
Novel anti-inflammatory agents - UCD researchers design a lipoxin that lasts

Our bodies’ basic defense against injury is inflammation. Even a small cut triggers a cascade of events, starting with the accumulation of blood at the site of damage, giving rise to the classic symptoms of redness, swelling and stiffness. White blood cells called neutrophils then migrate to the site of injury and absorb debris from damaged cells. Other cells known as microphages arrive to complete the clean-up process, initiating tissue repair.

Inflammation, however, has its dark side: unchecked, it can cause damage to the tissue. Cystic fibrosis is one of the many diseases now linked to an overactive inflammatory response. Others include asthma, rheumatoid arthritis and gum disease. Phagocytosis, where neutrophils are enveloped and digested by other cells, is a key event in the control of inflammation.

Photo of Dr Surendra Singh, Colm Duffy, Professor Pat Guiry and Dr Tasadaque Ali-Shah
Dr Surendra Singh, Colm Duffy, Professor Pat Guiry
and Dr Tasadaque Ali-Shah

A role for lipoxins
Regulating or halting the acute inflammatory response is a complex process involving “stop” signals. Biological molecules called lipoxins were first isolated in the 1980s. These molecules appear at the site of inflammation leading researchers to believe that they are involved in the process and thus may have potential therapeutic applications.

Some of the beneficial action ascribed to aspirin is now believed to be due to the formation of lipoxins. Both Lipoxin A4 and Lipoxin B4 have been detected in a variety of inflammatory conditions.

A multi-disciplinary team including Professor Pat Guiry of the Centre for Synthesis and Chemical Biology and Professor Catherine Godson, Professor of Medicine and Therapeutics at UCD Conway Institute are unravelling the story of inflammation and the role played by lipoxins in regulating the process.

“Lipoxins have been shown to promote phagocytosis of the neutrophils,” says Professor Guiry, Professor of Organic Chemistry at the UCD School of Chemistry and Chemical Biology. “However the therapeutic potential of lipoxins is limited by reactions with enzymes in our bodies which break them down.”

Nature doesn’t always know best
In the search for new therapies for diseases, researchers often look to nature for inspiration. The challenge for synthetic organic chemists is to create molecules which are superior to those found in the body. Professor Guiry’s research group have synthesised novel lipoxin-based molecules that help shed light on inflammation and offer a new approach to halting its damaging effects.

Professor Guiry believed that an analogue could be synthesised with the potency of the lipoxins, but with an improved “shelf-life” or chemical stability. “The challenge is to protect the molecules from the enzymes without altering their biological activity,” he explains.

With this goal in mind, they identified the region of the molecule which is essential for its biological function. By tailoring the non-essential region, they could effectively change the molecule’s chemical personality. The novel molecules would hopefully retain the functions of Lipoxin A4 and Lipoxin B4 while the metabolic reactions that break the molecule down would be blocked.

Biological testing of the lipoxin analogues has given promising results. “The Lipoxin A4 analogue shows a significant increase of phagocytosis, comparable with the naturally occurring lipoxin, while the Lipoxin B4 analogue also stimulates phagocytosis,” says Professor Guiry.

Future Directions
Further modification may increase the potency of the analogues by blocking other metabolic pathways. “Work is underway on the synthesis of other analogues and their subsequent biological evaluation,” he concludes. “Several chronic inflammatory conditions may be amenable to therapeutic intervention by stable synthetic lipoxin analogues.”


 

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