A molecule produced by the Southeast Asian liver fluke (<i>Opisthorchis viverrini</i>) could be the solution to nonhealing wounds. [CDC]” width=”60%” height=”60%” /><br />
<span class=A molecule produced by the Southeast Asian liver fluke (Opisthorchis viverrini) could be the solution to nonhealing wounds. [CDC]

It’s not every day that scientists are presented with the opportunity to turn a nasty critter into a potential life-altering therapeutic. For instance, being able to expedite the wound healing process could open care opportunities for people with diabetes and bedridden patients that were previously unavailable and positively affect their long-term effect care. Now, investigators from the Australian Institute of Tropical Health and Medicine (AITHM) at James Cook University have found that a molecule produced by the Southeast Asian liver fluke could be the solution to nonhealing wounds.   

Findings from the new study—published recently in the Journal of Medicinal Chemistry in an article entitled “Development of a Potent Wound Healing Agent Based on the Liver Fluke Granulin Structural Fold”—describes how the Australian scientists produced a version of the parasite molecule on a large enough scale to make it available for laboratory tests and eventually clinical trials. The molecule in question is called granulin, one of a family of protein growth factors involved in cell proliferation and secreted by the worms.

“It's produced by a parasitic liver fluke, Opisthorchis viverrini, which originally came to our attention because it causes a liver cancer that kills 26,000 people each year in Thailand,” explained study co-author Michael Smout, Ph.D., a research fellow at James Cook University. “We realized the molecule, discovered in worm spit, could offer a solution for nonhealing wounds, which are a problem for diabetics, smokers, and the elderly.”

The AITHM researchers found previously, as they were investigating a potential vaccine to protect people from the parasite, that granulin supercharged healing. The scientists looked for ways to produce the secreted molecule in sufficient quantities for large-scale testing. However, using traditional recombinant DNA techniques in bacteria wasn’t as straightforward as they had hoped.

“Unfortunately, granulin didn't perform well when we introduced it to Escherichia coli bacteria, so we couldn't use recombinant techniques to produce a testable supply,” noted senior study investigator Norelle Daly, Ph.D., a professor at James Cook University, whose research involves exploring the potential of peptides as drug candidates for therapeutic applications. “We had to go back to the drawing board and find a way to synthesize part of the molecule—to build our own version of designer worm spit.” 

Granulins are a family of protein growth factors that are involved in cell proliferation. An ortholog of granulin from the human parasitic liver fluke <i>O. viverrini</i>, known as Ov-GRN-1, induces angiogenesis and accelerates wound repair. [J Med Chem 2017;60:4258–4266]” width=”60%” height=”60%” /><br />
<span class=Granulins are a family of protein growth factors that are involved in cell proliferation. An ortholog of granulin from the human parasitic liver fluke O. viverrini, known as Ov-GRN-1, induces angiogenesis and accelerates wound repair. [J Med Chem 2017;60:4258–4266]

The research team worked to establish which parts of the molecule were critical to wound healing and to find a way to reproduce the active parts of granulin molecules. Using nuclear magnetic resonance (NMR) spectroscopy, the scientists revealed the molecule's complex shape: a string of amino acids bent into a twisted 3D shape that includes hairpin bends.

“In biology, the shape and fold of a molecule can be critical to its function,” remarked Dr. Smout. “Getting the fold right is important—it can be like the difference between throwing a well-folded paper plane or tossing a crumpled ball of paper.”

The research team tested numerous different segments and structures, concluding that the hairpin bends were the key.

“They're held in the twisted 3-D shape by disulfide bonds, and surprisingly we've found that by introducing an extra, nonnative, bond we can produce peptides that hold the right shape to promote healing,” Dr. Daly stated. “You could say we've found an extra fold that helps our peptide paper plane fly straight and target wounds.”

The lab-produced granulin peptides showed great promise in tests, driving cell proliferation in human cells grown in lab plates and demonstrating potent wound healing in mice. Now that they can mass-produce perfectly folded, wound-healing peptides, the researchers are looking for potential partners as they progress toward further testing and eventually clinical trials.

“We have plenty of work to do before clinical trials, but we're confident we have a very strong contender for what could one day be a cream that a person with diabetes could apply at home, avoiding a lengthy hospital stay and possible amputation,” concluded co-author Alex Loukas, Ph.D., professor at James Cook University, whose work includes the investigation of hookworm proteins to treat autoimmune and allergic diseases. “A take-home cream would be a great step forward for those with chronic wounds, and it would also save our health system a great deal of money.”







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