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Proteomics International Develops Process to ID Venom Peptides for Drug Development

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This story was originally published on May 6.

Spiders, snakes, and centipedes may be the stuff nightmares are made of, but for one Australian firm they may form the foundation for its future.

Last month, Proteomics International announced the development of Bioven, a process that links mass spectrometry with proprietary algorithms to determine peptide identify and predict their functions. Using this process, the company said that up to five times as many potential drug candidates can be recovered from venom than had been previously achieved.

In the first few months of operation, the company added, it was able to detect "several thousand" molecules and predict their potential bioactivity.

"We're extremely pleased with the number of molecules that we're identifying and the sheer number within each venom and in total," Proteomics International's managing director and co-founder Richard Lipscombe told ProteoMonitor recently. "And in terms of the analysis, we are in the process of evaluating leads that we've got from the process. We've been synthesizing a number of the peptides and they're currently undergoing validation."

While he declined to describe in detail the Bioven process, he said the company has been developing "methods at the front end" in order to look at proteomes more efficiently. The Bioven process is based on mapping the proteome of venoms using Proteomics International's proprietary algorithms to interpret the mass spectra and determine the protein sequence. New peptides and protein signatures are then analyzed against the company's in-house database of bioactive molecules to determine their applicability as potential therapeutic agents.

The method, Lipscombe said, has resulted in greater coverage of the venom proteomes that the company has been studying: While the scientific literature suggests about 50 to 100 peptides in any given venom, Proteomics International is seeing as many as 300 peptides, he said.

For now the firm is targeting peptides that may have therapeutic use as antimicrobials and analgesics as proof of concept for its technology. Antimicrobials are easy to test, Lipscombe said, while analgesics are a "well-known" target for venom-based therapeutics. He added that there is no limit to what the company can look at, "and we can just modify the search parameters and look in different areas if we wish."

R&D Dream Deferred

Proteomics International was founded in 2001 as a technology development firm. But like many other firms that started out as proteomics R&D shops, it found funding opportunities limited. Realizing it needed to branch into other work, it created a service business based around its expertise in protein analysis and mass spectrometry.

Today, the privately held firm's revenues come almost entirely from its CRO business, Lipscombe said. He declined to disclose any of the company's finances but said that during the past four years, the CRO business has been growing at an annual rate of about 40 percent.

Along with protein identification, the company's CRO business offers MRM analysis, differential expression analysis, N-terminal sequencing, and proteome mapping of organisms that "perhaps are not so well-characterized," Lipscombe said.

Among Proteomics International's CRO clients are Indian pharma firms Reliance Life Sciences and Natco Pharma, Aussie biopharmaceutical CSL Limited, and the Australian national science agency, the Commonwealth Scientific and Industrial Research Organisation.

The company has never lost sight of its R&D ambitions, however. "As we develop new things on our R&D platform, we sell them as services," Lipscombe said.

Its initial R&D work was targeted at plant-based peptides that had potential drug applications. As it tried to secure the rights from regional governments to collect flora to do its research, it also looked at classic biomarker analysis. An early project was directed at the identification of the fish species barramundi using Proteomics International's technology as an alternative to DNA-based identification methods.

"Some of the DNA tests out there are fine, but in some areas where the species is not so well known, there's a lot of work that's required to go down the traditional DNA route in designing primers and so on," Lipscombe said, "whereas [with] a protein-based system, you can just analyze the sample for what's there and away you go. We're finding it's quite a quick and robust method."

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The company launched a protein-based commercial test for species identification late last year — its first and only commercially available product. Lipscombe said that the technology was essentially the first iteration of the Bioven discovery method, developed and refined over the past three years. "The first part of what we can do there is [identification] of the species. The second part of it is identifying individual molecules."

Flora to Fauna

The firm never was able to gain the rights to do its plant-based peptide work because of reluctance on the part of the government to any research that may alter the natural landscape and environment, Lipscombe said.

But creeping, slithering critters armed with poisonous bites and stingers? "The rule of thumb seems to be that … most people are quite happy to see these things killed. Putting a boot to it or spraying it with some kind of insecticide is considered a good deed," Lipscombe said. "And if you want to work on it and analyze it, there are [fewer] concerns, whereas on the flora side there's a potential that it's going to be damaged or the environment is going to be severely disrupted, and there are tighter rules and regulations" working with plants.

When the firm switched its R&D focus to fauna from flora, it chose to concentrate on venom because of what it perceived to be growing market interest in the protein content of venom and its therapeutic uses, Lipscombe said. "Obviously, what's been holding the whole area up has been delivery."

In a study published online last month in the Proceedings of the National Academies of Science, its authors wrote that disulfide-rich peptide venoms from animals such as snakes, spiders, scorpions, and some marine snails are "one of nature's great diversity libraries of bioactive molecules." The peptides are of "considerable interest because of their ability to potently alter the function of specific ion channels," but to date only a "small fraction of this immense resource has been characterized because of the difficulty in elucidating their primary structures," the researchers, led by Brian Chait who runs a mass spec lab at Rockefeller University added.

In their study, they describe a de novo protein sequencing method they developed to gain information about the mature peptide toxin components of crude venom samples. Their mass spec-based strategy combines electron transfer dissociation with a targeted chemical derivatization component "to increase the charge state of cysteine-containing peptide toxins," they wrote. The authors reported that they were able to obtain the full sequences for 31 peptide toxins, using 7 percent of crude venom from the venom gland of a single cone snail.

Proteomics International is investigating venom from about 15 species with a particular focus on arthropods that have been mostly ignored by the scientific community. Because of its location in western Australia, and the "uniqueness" of the bio-species in the area the company's attention has been on creatures found in the region, Lipscombe said.

Government restrictions prohibit the company from working on species that are threatened or endangered, and when the company started its work, it had to submit to the government for approval a list of creatures it wanted to research. About 50 creatures have been approved, and any additional members to that list would similarly need the OK of the government.

Among the venoms that are being analyzed by Proteomics International are that of a Wall spider and Huntsman spider that are indigenous to Australia, as well as Jack Jumper ants.

Under the terms of the agreement Proteomics International has with the Northern Territory government, the government would receive royalties from any discovery by the company leading to a commercial product or services, Lipscombe said.

If any of the venom work leads to peptides that can be developed into a therapeutic, the company would license the peptide out. "We don't believe we have the firepower at the moment to turn them into drugs, and we recognize our skill set is in the discovery end of the pipeline," Lipscombe said.

Though the firm has no plan on licensing out the Bioven method to drug manufacturers, he did not rule that out. "I think with something like that, it would come down to the offer," he said.

The preliminary success of Bioven, he said "is a major milestone for the company in terms of what we set out to do." The next step would be to expand the range of venoms in its research portfolio, and possibly even return to its original idea of researching flora-based peptides. "In terms of what we would do as a company, the model still remains a combination of a contract research organization and drug developer, so we would continue to expand both areas of our business," Lipscombe said.

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