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Cryo-EM in Drug Discovery

Cryo-EM provides new 3D views of therapies and their targets

Mike May, PhD

Mike May is a freelance writer and editor living in Texas.

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The structure of a drug impacts its efficacy and safety. Scientists can analyze that structure at angstrom-level resolution by quickly freezing a sample to a cryogenic temperature, which is below –150°C, and imaging it with electron microscopy. This cryogenic electron microscopy (cryo-EM) “has many applications in drug discovery,” says Giovanna Scapin, chief scientific officer at NanoImaging Services in San Diego, CA. 

Scientists can use cryo-EM to analyze a drug target’s three-dimensional structure or to characterize a drug carrier, such as lipid nanoparticles or adeno-associated viruses. The 3D-structure information can be used, for instance, to characterize how a drug might interact with a target.

In one example Scapin references, a team of scientists led by Pavel Nikitin, PhD, senior director at Immunone, used cryo-EM to create an antibody cocktail against variants of the SARS-CoV-2 virus. “Low resolution-electron density maps generated by cryo-EM were initially used to assess the mode of action of the three antibodies in the cocktail and to identify one antibody with a clearly different mode of action,” Scapin explains. “High resolution–single particle analysis of said antibody in complex with the COVID spike receptor binding domain allowed for the definition of the antibody epitope and the explanation, at the atomic level, of its activity.”

Overcoming crystallization challenges

In some cases, cryo-EM provides structural information that could not be obtained with other methods, such as crystallography. “Cryo-EM has allowed us to structurally enable protein systems which are not as amenable to crystallization, such as large protein complexes and membrane proteins,” says Pamela Williams, senior director at Astex Pharmaceuticals in Cambridge, UK. “We then generate structures of these proteins in complex with small molecule ligands, which allows our chemists to optimize these interactions with the end goal being the design of a potent drug.”

To create the most effective drug, scientists need to understand its structure as well as that of the intended target. “In the absence of the protein-ligand structure, understanding how modifications to the ligand can impact potency can be challenging,” Williams explains. 

Improving the process

Although Williams and her colleagues can routinely determine the structure of a protein-ligand complex with cryo-EM, they’d like to do it faster. “The optimization can be a long and often non-linear process,” Williams says. “There are lots of parts of the process that can still be improved.”

For example, Williams and Scapin would like to see improvements in getting a sample ready for imaging. “The one aspect that still presents some limitations in single-particle analysis and characterization is the process of getting the sample frozen on a grid in a fast and, most importantly, reproducible fashion,” Scapin says. “The necessity of identifying conditions for each sample screened, and the need for making multiple grids of the same condition in order to obtain a usable one, is the current limiting step in what has the potential to be a fast and information rich technique.”

Despite some ongoing challenges, cryo-EM clearly gives scientists new ways to make better drugs for the future, and that capability is likely to improve even more.