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Indiana Firm Developing Technology to Study Little-Understood Disordered Proteins

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As a field of research, the study of disordered proteins is still comparatively in its infancy, but Molecular Kinetics is betting its future on it.
 
Formed in 1983, the Indianapolis-based shop began as the exclusive North American distributors for kinetic instruments manufactured by French firm Bio-Logic. But about a decade ago, Keith Dunker, then a bioinformatics professor at Washington State University, became interested in disordered proteins and began developing algorithms to predict the probability of a protein being disordered.
 
Thus began Molecular Kinetics’ transformation into a company trying to turn a profit from a field of research that only recently has been accepted by the scientific community.  
 
“We are basically a company dedicated to the development of turning protein disorder into any application form,” said Ya-Yue Van, president of the company and wife of Dunker, a consultant to Molecular Kinetics and now the director of the Indiana University School of Medicine’s Center for Computational Biology and Bioinformatics.
 
“I want to move into proteomics. I want to be known as the one-stop shop for all protein disorder applications,” she added.
 
Where are the Tools?
 
Until recently, the very existence of disordered proteins, which don’t exhibit a stable secondary structure, was largely dismissed by many in the biological community, which has traditionally ascribed a protein’s function to its structure. The broader scientific community began accepting the concept of such proteins, also called intrinsically unstructured proteins, only within the past few years.
 
Even today, “There are still a number of people who think that these are some kind of artifacts, and if we had the conditions right, somehow the protein would be folded,” Dunker said.
 
The result is that little research has been conducted in the field. A keyword search of PubMed for the terms “unstructured protein” and “disordered protein” came up with only 165 results. Of the approximately 30,000 to 40,000 gene-coding proteins, up to 40 percent have been estimated to be disordered. To date, however, only 472 have been identified and catalogued in the Database of Protein Disorder, according to DisProt’s website.
 
When Dunker first began research in the field 10 years ago, he said, it was apparent that disordered proteins play an important biological role in cell signaling, but information about the proteins was scattered and, well, disordered.
 
So he, a colleague, and their students began developing algorithms “to take an amino acid sequence and then predict whether it’s going to be a folding sequence or a non-folding sequence,” he said.
 
But both he and Van saw that there was a serious deficiency in the tools available to study disordered proteins.
 
“All the high-tech tools are dedicated to the ordered regions like crystallography — you’ve got equipment out the yin yang exploring that,” Van said. “But in the protein disorder field, because they didn’t think it [was] a field, nobody bothered to develop a useful tool.”
 
The use of proteomics technologies and methods for the analysis of disordered proteins has happened only within the past two years. Among those who are developing proteomics technologies for analyzing such proteins are researchers at St. Jude’s Children’s Research Hospital in Memphis, Tenn., who last fall said they had developed a mass-spectrometry based method for identifying disordered proteins [See PM 10/19/06].
 
Territory That’s Virgin
 
Even while the scientific community was still debating whether disordered proteins actually existed, Van and Dunker saw a business opportunity before them.
 
“I said, ‘This is virgin territory, and there’s a lot of business opportunity [there],’” Van said. “I didn’t know what [would] come out of it [but] you throw all kinds of seeds and see what comes out. It sounds kind of silly, but literally that’s what we were thinking.”
 
With Small Business Innovation Research grants from the National Institutes of Health, the company built disease databases with the goal of finding proteins associated with a disease, then figuring out whether protein disorder played a role in the disease process.
 
Using “all the existing databases that we could get our hands on,” including SwissProt and the Protein Identification Resource, Dunker said, the company eventually built databases for five disease categories: neurodegenerative; diabetes; cardiovascular, cancer; and automimmune.
 

“All the high-tech tools are dedicated to the ordered regions like crystallography — you’ve got equipment out the yin yang exploring that. But in the protein disorder field, because they didn’t think it [was] a field, nobody bothered to develop a useful tool.”

As they built their databases, Dunker and other Molecular Kinetics scientists paid particular attention to whether proteins had structured and unstructured regions and what roles any unstructured regions may have in the activities ascribed to the protein.
 
In doing so, they began noticing that in some protein-protein interactions that were being blocked by drug candidates, one of the partners in each case underwent a disorder-to-order transition when binding to its structured component.
 
That chance observation led to a possible new pathway for drug discovery.
 
“Our disordered database itself is not that useful,” Van said. “But we have also developed 13 software [packages for use with] the database, and some of them became critical tools in our drug discovery. At the time we did it, we had no clue, but as the data came up, they all pointed to a new way of finding new drug targets that all drug companies currently have ignored.”
 
In addition, Molecular Kinetics has developed a sample-prep tool called AquoProt for dissolving proteins. According to Van, AquoProt has 150 vectors, meaning it can dissolve a protein 150 different ways. The product works by adding a flexible disordered polypeptide chain to the N-terminus or C-terminus of the protein of interest.
 
“We fuse a floppy piece onto a protein … which has a very large surface area. It has a very high solubility, and it tends to increase the solubility of whatever it’s attached to,” Dunker said.
 
Molecular Kinetics is beta testing AquoProt with a “major” drug firm, said Van, though she declined to provide further details.
 
Despite being in business for more than 20 years, the company is operating essentially as a start-up, and Van said that it will need venture capital funding for development of its technologies. The VC environment for protein- and proteomics-focused businesses may be tepid, but Van is undeterred.
 
Eventually, she said, the company will license its software and database and forge collaborations with drug firms for drug discovery research. It also plans to provide protein analysis services.
 
“When we first started delving into this protein disorder area, we had no clues about tools,” she said. “We just thought about developing a bunch of software. I would never imagine we would be heading toward the mainstream in new target development for drugs.”

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