In an illustration of how techniques for studying the proteome are finding an increasingly wide array of potential applications in drug discovery, AstraZeneca last week agreed to work with Ambit Biosciences to use the company’s phage display and affinity chromatography technology to identify proteins that interact with specific small molecules.
Most companies using proteomics for drug discovery first try to identify differentially expressed or otherwise disease-associated proteins before designing small molecules or antibodies against them. In contrast, AstraZeneca and San Diego-based Ambit will take small molecules that AstraZeneca has found to have a particular pharmacological effect in preliminary assays, and try to identify the protein targets of the small molecules.
Armed with the protein target, researchers can then apply rational drug design techniques to modify the small molecule so that it more specifically interacts with the target protein. In theory, this will enable AstraZeneca and Ambit, which has its own in-house drug discovery program, to tailor the small molecule to avoid potentially toxic interactions with other proteins in the cell.
The companies did not disclose financial details of the deal, nor the number of AstraZeneca’s small molecules that Ambit would study.
Ambit has licensed technology for “display cloning” from the Yale University lab of Dave Austin, an associate professor of chemistry who studied under Stuart Schreiber, a renowned chemical biologist at Harvard University.
The technique works much like conventional phage display, by allowing Ambit to insert large collections of genes into the phage genome, which produce folded proteins or protein fragments on the surface of the phage particles. The company can then screen the displayed proteins with small molecule probes attached to beads or other substrates, and use affinity chromatography to fish them out.
Ambit claims it can produce phage libraries containing up to 10,000 proteins, and can perform up to 200 of the small molecule screens per month. With part of the $12 million in private capital that the company has raised so far, it plans to automate several steps in its proteome scanning technology, which should further increase the experimental throughput.