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Biognosys Licenses ETH Zurich Tech to Add to Drug Research Offerings


NEW YORK (GenomeWeb) – Targeted proteomics firm Biognosys said this week that it has licensed the Limited Proteolysis (LiP) technology developed by the lab of Swiss Federal Institute of Technology Zurich Professor Paola Picotti.

The method uses mass spec-based analyses of protein proteolysis patterns to assess structural changes on a proteome-wide scale and could be useful for applications including studies of drug binding and drug target deconvolution, said Biognosys Director and CEO Oliver Rinner.

Rinner said that Biognosys has begun offering the method as one of its proteomics services to a limited group of customers and is now working to develop it as a service available to its full customer base. He suggested that it will help flesh out the company's current service offerings, which are primarily focused on measuring proteome expression changes using Swath-style data-independent acquisition mass spectrometry.

"We believe that understanding proteome changes is an important piece of information, and mostly we do this on the protein expression level, if proteins go up and down," Rinner said. "But there is certainly a different level to it, as well, and that is the structural level."

"When we do protein expression profiling projects with customers, the [goal] is that it goes beyond a single project," he added. In the case of drug studies, "looking at protein expression changes can give you insight into [affected] pathways, but in many cases it is obvious that people would also love to know directly what the protein binding partners are. So, this is an attempt to provide a broader spectrum of answers to such questions."

The LiP approach was developed in the lab of ETH Zurich Professor Paola Picotti, who is a scientific advisory to Biognosys and was also, with Rinner, a post-doc in the lab of ETH Zurich researcher Ruedi Aebersold. Biognosys was spun out of Aebersold's lab in 2008.

The LiP method combines digestion with a broadly specific protease followed by a standard mass spec-based proteomics workflow to assess structural changes on a proteome-wide scale. The basic notion underlying the approach is that in the initial digestion step, the protease will cleave proteins only at sites that are accessible, left exposed by whatever structural conformation it happens to be in at the time of analysis. When a sample of interest is treated with, for instance, a drug, the proteins that bind to this molecule will undergo a structural change, and this will be reflected in changes where the protease is able to cleave the protein.

By following this initial digestion step with standard trypsin digestion and mass spec analysis, researchers can compare the peptides generated in treated and untreated samples and, based on changes in the peptides produced, determine which proteins had their structures altered by the treatment in question.

From a commercial standpoint, the method is most obviously useful for drug studies, as it could allow researchers to identify proteins that bind to an agent of interest.

Small molecules drugs that bind intracellularly are perhaps the best candidates for the approach, Rinner said, though he added that it could potentially be applied to looking at binding of extracellular proteins, as well.

"Some applications are really a good fit and have been proven and others we are still developing," he said.

In the 2014 Nature Biotechnology paper in which Picotti and her colleagues introduced the approach, the researchers looked at the effect of changes in nutrients on the structure of yeast proteins. Measuring around 1,000 proteins they identified roughly 300 that underwent conformational changes in response to changing nutrition.

Last week, she and her colleagues published a paper in Science in which they used the LiP method to measure the thermal stability of proteins on a proteome-wide scale, looking at more than 8,000 proteins in Escherichia coli, Saccharomyces cerevisiae, Thermus thermophilus, and human cells.

Though not directly related to Biognosys's interest in the technique, the LiP approach provided several insights into cellular heat sensitivity, including the finding that cell death due to temperature stems not from broad loss of protein function across the entire proteome, but from the loss of a smaller, key set of proteins. Additionally, they found that heat-stable proteins were typically high abundance and less likely to aggregate, a discovery that the authors noted supports and expands theories of "translational robustness" developed from genomic data that hold that more high abundance proteins are better able to tolerate translational errors.

While Biognosys is primarily interested in drug research applications, the Science study "is nice because it shows that this structural proteomics paper can address many aspects [of protein behavior]," said Rinner, who was not involved in the work.

He suggested that Biognosys's focus on DIA mass spec also made the LiP approach a good fit for the company, noting that DIA mass spec's high reproducibility would help researchers separate true hits from false ones.

"I think what will be important is, on the one hand, to have high sensitivity because you want to find the few peptides that really change, and on the other hand, it is a bit of a needle in the haystack kind of problem, so it is very important to have high specificity, otherwise you will be flooded with potential [but false] hits," he said. "So, both fit well with the DIA technology, especially the specificity part, the fact that you can really have high reproducibility."

Based in Schlieren, Switzerland, Biognosys last year opened a US office in Cambridge, Massachusetts. According to Rinner, the company has for several years done the majority of its business in the US and is planning to expand its Cambridge office from its current size of five people.

Currently, the company's US presence is focused primarily on business development, with all mass spec work done in Switzerland, though Rinner said it is possible Biognosys will in the future add some US-based mass spec capabilities.