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SGX and Graffinity Attempt to Marry Protein Crystallography, Small Molecule Arrays


Pharmaceutical companies have long relied on x-ray crystallography to help refine their candidate small molecule drugs, but a deal signed last week between Structural Genomix (SGX) of San Diego and Heidelberg-based Graffinity may be the first to combine the new breed of high-throughput protein crystallography with array-based approaches to finding drug leads.

Graffinity, which has developed arrays of up to 10,000 combinatorially synthesized small molecule fragments, has agreed to screen its libraries for fragments that interact with undisclosed protein targets supplied by SGX.

SGX will then attempt co-crystallize any protein-fragment complexes that interact, and determine their three-dimensional structure with synchrotron x-ray crystallography. In theory, information on the structure of the complexes will lead to compounds that bind specifically to a given protein target.

“There’s every reason to believe from work that’s been done on a smaller scale that this approach is very useful,” said Eric de La Fortelle, director for business development at SGX. “On the scale that we are approaching this, which is the scale of several dozens of crystal structures, it’s probably going to be more useful.”

For the moment, however, the purpose of the collaboration is to determine how much synergy the two technologies have, de La Fortelle said. The two companies first began discussing the possibility of working together at a conference three or four months ago, where SGX’s vice president for chemistry, Douglas Livingston, met with Graffinity CEO Dirk Vetter.

Neither company would disclose the financial details of the arrangement, but de La Fortelle conceded that SGX and Graffinity both have stakes in any resulting intellectual property. The two parties have not decided whether to publish or attempt to commercialize the data that come out of the immediate collaboration, he said.

De La Fortelle wouldn’t disclose the nature of the targets the two companies are initially studying, saying only that the proteins were easily expressed in bulk quantities and that SGX had already determined the individual protein structures. “They are good workhorses to [get] quick results in this collaboration,” he said.

Graffinity will take these protein targets and wash them across its arrays of small molecules, which are tethered to gold-plated surfaces, said Dirk Harraeus, a spokesman for Graffinity. To detect interactions between a protein target and the small molecule fragments, Graffinity researchers have developed a surface plasmon resonance technique that does not require labeling the protein, he said.


Building Up Small Molecules

The potential benefit of working with Graffinity’s technology platform, said de La Fortelle, is that its screening technique can detect several different small molecule fragments that each interact — however weakly — with the protein target. Crystallizing and determining the structure of the different complexes should enable the researchers to build larger organic molecules that bind specifically to the protein target, he said.

“Unless we’re very lucky, none of these fragments will directly give us a lead compound for drug discovery,” de La Fortelle said. “The huge interest of what we’re doing is that one of these weak binders can be combined chemically with another weak binder and the two together can give us something that is both potent and selective.”

Graffinity has partnerships with pharma companies such as Aventis, Boehringer Ingelheim, and a recently announced collaboration with Celera. Unlike those deals, however, the collaboration with SGX allows Graffinity researchers to use the x-ray crystallography data to refine their libraries of small molecule fragments and search for particular moieties that interact strongly with a protein target, said Helmut Kessman, Graffinity’s vice president for business development.


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