Séminaire IBS : From Atoms to Applications : Cryo-EM’s Journey Through Industrial Drug Development

Par Dr Chiara Rapisarda (Sanofi, Paris)

The rapid advancement of cryo-electron microscopy (cryo-EM) has established it as an essential tool in contemporary structural biology and drug discovery, providing high-resolution insights into complex drug-target interactions. To fully leverage cryo-EM’s potential in an industrial setting, focused efforts are required to enhance the efficiency and success rate of structure determination, especially for challenging therapeutic targets.

This presentation will detail two key methodological and technological innovations developed at Sanofi that streamline the cryo-EM pipeline.

The first is "crai" (cryo-EM antibody identification), a machine learning-based ChimeraX bundle. This computational tool is designed to automate the robust detection, classification, and precise orientation analysis of antibody fragments (Fabs, Fcs) directly within cryo-EM density maps. By replacing manual fitting and interpretation, "crai" significantly accelerates the structural analysis of therapeutic antibody complexes.

The second innovation addresses sample preparation for difficult-to-resolve targets. We introduce the "Fabuoulous" mutation, a specific modification within an antibody Fab fragment that optimizes its properties for cryo-EM. This modified Fab can be used as a stable, minimally intrusive scaffold to facilitate the structure determination of target molecules without the need for large, conventional fiducial markers or affinity tags. This approach simplifies sample requirements and yields higher-quality maps for small or conformationally dynamic targets.

These innovations highlight a dual strategy—combining advanced machine learning with targeted biochemical engineering—that is critical for maximizing the efficiency and impact of cryo-EM in accelerating the structural-guided design of novel therapeutics at Sanofi.

Hôte : Franck Fieschi (IBS/Groupe Membrane et pathogènes)