Peptides derived from Ov-GRN-1 (orthologue of granulin) are leads for wound healing therapeutics, as they are likely less immunogenic than the full-length protein and more convenient to produce.
A molecule produced by a Thai liver parasite could be the solution to those non-healing wounds. Globally, every 30 seconds a diabetic has a limb amputated due to a non-healing wound. Scientists from the Australian Institute of Tropical Health and Medicine (AITHM) are now able to produce a version of the molecule on a large enough scale to make it available for laboratory tests and eventually clinical trials. The molecule is granulin, one of a family of protein growth factors involved with cell proliferation.
“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,” parasitologist Dr Michael Smout said. As part of their work on a potential vaccine to protect people from the parasite, Dr Smout and colleagues established that the granulin it produces has a hidden talent – it supercharges healing. “We realised the molecule, discovered in worm spit, could offer a solution for non-healing wounds, which are a problem for diabetics, smokers and the elderly,” he said.
With fellow researchers Dr Smout has been investigating ways to produce granulin in sufficient quantities for larger-scale testing. The team first tried recombinant DNA techniques, effectively inserting granulin into bacteria, with the aim of producing plentiful supplies of a reliable copy of the molecule. “Unfortunately, granulin didn’t perform well when we introduced it to E. coli bacteria, so we couldn’t use recombinant techniques to produce a testable supply,” said Professor Norelle Daly.
“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,” she said. They 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 (peptides). NMR spectroscopy revealed the molecule’s complex shape: a string of amino acids bent into a twisted 3D shape that includes hairpin bends. After testing different segments and structures, the team concluded that those hairpin bends were the key.
“They’re held in the twisted 3D shape by disulfide bonds, and surprisingly we’ve found that by introducing an extra, non-native bond we can produce peptides that hold the right shape to promote healing,” Professor Daly said. The lab-produced granulin peptides have shown 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 towards 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 diabetic could apply at home, avoiding a lengthy hospital stay and possible amputation,” said Professor Alex Loukas. “1 in every 7 diabetics in Australia will have a non-healing wound at some point, and many suffer amputations as a result. It’s estimated the long hospital stays involved in treating chronic wounds cost our healthcare system AU$3.7 billion per year.” https://www.jcu.edu.au/news/releases/2017/may/designer-worm-spit-supercharges-healing http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b00047
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