Vol 9. Issue 31 / October 19, 2009

Team Awarded $3.9 Million "Transformative" Federal Grant to Develop New Compound Screening Platform

By Eric Sauter and Mika Ono

A pair of scientists from The Scripps Research Institute, one on each coast, has been awarded a five-year $3.9 million grant from the National Institutes of Health (NIH) to develop a new technology to accelerate the search for new protein ligands – compounds that bind to proteins and alter their function.

Current screening technology, which is slow and expensive, has caused what the NIH calls a "major bottleneck" in the search for these basic tools that are key for the broader study of biological processes and that lay the groundwork for development of most drugs.

The grant, awarded as part of the NIH's new Roadmap Transformative R01 Program, will be shared between the laboratories of Tom Kodadek, a professor in the Scripps Research Departments of Chemistry and Cancer Biology in Jupiter, Florida, and Benjamin Cravatt III, professor and chair of the Department of Chemical Physiology and member of The Skaggs Institute for Chemical Biology and Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute at Scripps Research in La Jolla, California.

"Ben and I are extremely pleased to win this highly competitive award and to be among the first selected for the new Transformative Grant program from the NIH," Kodadek said. "This is a perfect example of the tremendous collaborative possibilities available within Scripps Research. We worked on the proposal together and the fact that we're both part of the same national institution will make the work that much easier as we move ahead."

Cravatt added, "This project is a good reflection of what those of us at Scripps Research in La Jolla and in Florida are trying to accomplish – fostering collaborative interaction and working on complimentary research projects. This will help cement the strong working relationship between our two campuses."

The NIH Roadmap Transformative R01 (T-R01) Program awards were launched this year to support exceptionally innovative, high risk, original, and/or unconventional research projects that have the potential to create or overturn fundamental scientific paradigms.

"The appeal of the Pioneer, New Innovator, and now the T-R01 programs, is that investigators are encouraged to challenge the status quo with innovative ideas, while being given the necessary resources to test them," said NIH Director Francis S. Collins, "The fact that we continue to receive such strong proposals for funding through the programs reflects the wealth of creative ideas in science today."

Two Innovative Methods and a Cab Ride

The new Scripps Research project will combine two separate technologies from each laboratory – a peptoid library synthesis and screening platform developed in the Kodadek laboratory and an activity-based protein profiling system developed in the Cravatt laboratory.

Kodadek's screening platform involves the creation of vast libraries of peptoids (peptoids are synthetic molecules that are similar to peptides, compounds that when joined together make up proteins) displayed on microscopic beads that are screened against fluorescently tagged proteins that light up after binding with a high affinity, highly selective ligand.

"Our screening technology simulates the cellular environment," Kodadek said, "because the tagged proteins, which represent only a small fraction of the total, are mixed in with un-tagged competitors. There is a specificity filter built into the process from the beginning."

The Cravatt Laboratory has pioneered the Activity-Based Protein Profiling technology, which allows scientists to identify protein classes based on their activity. The basic technology attaches a single label or probe to proteins from a particular subset of the proteome, which allows access to what are considered low abundance proteins and makes it ideal for massive parallel screening experiments. So far, Activity-Based Protein Profiling probes have been developed for more than a dozen distinct enzyme classes. Cravatt's technology makes it possible to target what he calls "interesting classes of proteins" but in a highly parallel fashion – hundreds of screens at a time of those multi- million member peptoid libraries.

Although both scientists have known one another for some time, many of the details of the collaboration were worked out on a cab ride from England's Heathrow airport to London last summer.

"Tom and I had an editorial board meeting in London, and shared a cab from the airport," Cravatt said. "The fact that Tom had recently joined Scripps Florida helped get us energized about the project." "It's true," Kodadek added. "The ideas behind the grant proposal just popped out of that ride."

A Transformational Marriage

The combination of the Kodadek and Cravatt advanced technologies will allow the screening of massive peptoid libraries (1-10 million synthetic compounds) in parallel fashion, a novel strategy that the scientists predict will increase the rate of ligand discovery by several hundred times over current methods.

"The gist of our proposal is quite simply marrying these two beautifully worked out technologies," Kodadek said. "We have a good track record on both sides, plus we're building off these innovative platforms, so if this works, and I'm certain it will, it will definitely be transformational."

That transformation, when it comes, should result in more lead drug candidates, Kodadek said, because while the scientists' success rate has been lower than those using current high throughput screening technology, the quality of the ligands identified has been significantly better. Some of this is due to the fact that simple synthetic compounds like peptoids have many advantages over other ligands such as antibodies. They can be modified easily for attachment to surfaces and can be produced in relatively large amounts at lower cost and rather quickly – a multi-million member peptoid library, for example, can be created in around three days.

"The way most science works today," Cravatt said, "is that researchers tend to huddle around those areas where there are tools available. By combining our technologies, we will have a streamlined, unbiased way to identify high quality protein ligands and that will give us access to a large part of the proteome that others can't study right now because the current technology is inadequate."



Send comments to: mikaono[at]scripps.edu



"Ben and I are extremely pleased to win this highly competitive award and to be among the first selected for the new Transformative Grant program from the NIH," says Professor Tom Kodadek.



"This will help cement the strong working relationship between our two campuses," says Benjamin Cravatt, chair of the Department of Chemical Physiology. (Photo by BioMedical Graphics.)