Proteins have two defining properties: structure and mobility. Although many companies are currently elucidating protein structure using x-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, few are studying how proteins and their domains move during physical interaction with other molecules. Signature Bioscience has sought to remedy this situation using its technology platform, multipole coupling spectroscopy (MCS). (Click here for company profile.)

First conceived by John Hefti, MCS involves probing proteins with microwaves and recording the resulting electromagnetic spectra, creating a unique “signature” for each protein. The protein is then combined with a small molecule, spliceosome, or cell, and a new signature obtained. Changes in the protein's signature may reflect various characteristics of the protein, including domain movements, enzymatic activity, conformational change, or denaturation. MCS can therefore be used to determine whether a drug candidate binds to a protein target, and can detect cellular alterations such as changes in morphology, ion redistribution and flux, and protein redistribution within a cell.

Hefti says that MCS can also determine if two enzymes with similar amino acid sequences have radically different structures and therefore different functions, or whether two enzymes with dissimilar sequence have similar structures and therefore related functions. Such information is valuable when mapping protein–protein interactions, in which a crystallographic approach would be both difficult and time-consuming.

The technology itself is not original; it is identical to methods used by computer chip engineers to determine the purity of semiconductor crystals. However, Signature Bioscience has been able to eliminate what had been the main limitation to the technique: the background noise generated by water in the solutions of proteins. A similar problem arises with the noise created by the cell membranes in which most important drug targets are embedded, but Hefti is confident that the company will eventually overcome this difficulty.

Signature Bioscience is also developing software tools that can translate the raw data into valuable information. Within two years, revenue will be generated by licensing out a “package” of database and software for protein mapping and drug screening of the 100 protein families that are the most popular drug targets. Some revenue with be generated through the marketing of spectroscopes—manufactured with a partner—but Signature Bioscience's main profit generator will be target-validation collaborations. The company currently has three collaborations, including a deal with Sunesis Pharmaceuticals (Redwood City, CA) to determine small-molecule inhibitors of protein–protein interactions within inflammation pathways. By the end of the year, Hefti hopes that Signature Bioscience will be able to carry out 1,000 assays per day per machine, further attracting customers to its unique database.