A ‘triple win’

ILLKIRCH, France—Taking a giant step toward developing more powerful drugs in less time and at cheaper costs, French contract research organization (CRO) NovAliX has partnered up with Hillsboro, Ore.-based FEI to bring commercial cryo-electron microscopy (EM)-based structural analysis services to its global pharmaceutical and biotech clients. Having access to cryo-EM gives customers an edge on the market with its three-dimensional view of structures under conditions much closer to the native intracellular environment, the companies say.

Cryo-EM has quickly become one of the most important techniques used by structural biologists today to obtain 3D information about protein structures, the partners add. When combined with traditional methods for structure determination, such as X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, the resulting models can reveal the structure of complex, dynamic molecular assemblies down to the scale of individual atoms.

The collaboration combines NovAliX’s integrated cryo-EM workflow based on a transmission electron microscope (TEM) and FEI’s combined application, training and support with onsite personnel.

“There is a growing demand for structural studies from the pharmaceutical industry, driven by the need for a deeper scientific understanding and because of stronger regulatory constraints,” Denis Zeyer, CEO of NovAliX, stated in a news release.

In the field of biologics, EM analysis has proven to be capable of delivering critical information for antibody selection, epitope mapping and formulation, Zeyer said. With small-molecule research programs, cryo-EM can be uniquely valuable to obtain structural information on multiprotein complexes or membrane proteins, which is key to understanding the structure-function relationship.

“During the latest NovAliX conference, we have witnessed the interest and the relevance of biophysical tools in drug discovery,” Zeyer said, “so this new offering will nicely complement our structural biology and biophysical platform that includes X-ray, NMR, surface plasmon resonance and native mass spectrometry. Now with cryo-EM available, NovAliX scientists are able to deliver critical insights into the biology of protein complexes. Indeed, we will be able to fit X-ray structural results of individual proteins with a global structural view of the complex obtained by cryo-EM, which is otherwise not easily accessible.”

Zeyer tells DDNews, “Cryo-TEM now can be used for the structure determination of membrane bound proteins like ion channels up to near atomic resolution, revealing the side-chain arrangements required to understand their gating mechanisms. Hence, cryo-TEM is seen by NovAliX as a powerful alternative for doing structure-based drug design on this protein family.

X-ray crystallography “is the gold standard for structural studies, but is limited for the analysis of complex molecular target like membrane bound proteins or large molecular assemblies as the crystallization of such proteins is highly challenging,” Zeyer said. “Integration of the cryo-TEM in our technology portfolio and workflow will enable us to work on such targets and allow us to provide invaluable structural information for the successful development of novel clinical candidates.”

Peter Fruhstorfer, vice president and general manager of the Life Sciences business at FEI, also speaks positively of the benefits of cryo-EM models. He stated that cryo-EM 3D models “allow us to see and understand the workings of protein-based molecular machines that we could not analyze before because they were too large and complex or were resistant to the preparations required for other techniques.”

“The power and value of cryo-EM based structural analysis is evident from the quality of recent publications by academic and industry researchers,” according to Fruhstorfer. “This collaboration with NovAliX is an important step in the broader commercialization and industrialization of the technology.”

The recent advances in cryo-EM “put this method at the forefront of life sciences, and now enables scientists to look into large protein complexes at near atomic resolution,” Fruhstorfer tells DDNews. “It opens a new perspective in the field of drug discovery.”

For the first time, “therapeutic relevant protein complexes can be studied in their native state,” he adds. “The partnership between NovAliX and FEI helps to make cryo-EM structural studies accessible for the pharmaceutical industry in order to gain higher success rates and effectiveness.”

In addition, “single-particle cryo-TEM can be used to map epitopes at intermediate resolution to understand precisely how therapeutic antibodies bind their targets, allowing researchers to only focus X-ray studies on the most promising antibodies for high-resolution studies as that approach is time consuming,” Fruhstorfer said.

This is the first partnership between FEI and any CRO company, according to Fruhstorfer, who notes that this model of partnership “makes cryo-EM accessible and more affordable to larger number of NovAliX clients.”

“At present, the role of CROs is critical because of a strong increase of outsourcing in the global pharmaceutical industry in an effort to access novel technology, increase the critical capacities and shorten the time of the drug development process,” Fruhstorfer says. “FEI is in the unique position to develop its technology and expertise while enabling our CRO partner, NovAliX, in serving better its pharmaceutical customers.”

“This is indeed a triple-win combination for FEI, NovAliX and our clients,” he concludes.