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Cryo-EM Advances Are Good News for Drug Discovery

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Cryogenic electron microscopy (cryo-EM) is a key technique in the structural biologist’s armory. Whilst it has historically been regarded as the low-resolution brother to the likes of X-ray crystallography and nuclear magnetic resonance (NMR) in structural determination, exciting recent developments are seeing this situation change. Two preprint papers have recently been published from groups at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany and the Medical Research Council Laboratory of Molecular Biology (MRC-LMB) in Cambridge, UK, demonstrating atomic resolution cryo-EM structures. This is a huge leap forward for areas like drug discovery that relies heavily on accurate structure determinations for the continued and focused discovery of therapeutic targets and development of effective active molecules.

We spoke to Raymond Schrijver, Senior Director of Pharma at Thermo Fisher Scientific, about why cryo-EM is so important to drug discovery and ways in which the technique is becoming more accessible.

Karen Steward (KS): Why is structural biology so important in drug discovery?

Raymond Schrijver (RS):
One of the key challenges in drug discovery is accurate prediction for properties of new molecules. To arrive at a drug candidate, thousands of compounds must be synthesized over several years and still a significant portion of drug discovery projects fail due to poor properties of drugs.

Structural biology delivers near-atomic resolution structural insights on how a compound interacts with its drug target, revealing important information on structure-activity relationships. This minimizes the number of compounds that must be synthesized, leading to high-efficacy drug candidates faster. In other words, structure-based drug discovery methods can reduce the time, cost as well as failure rates of this process and are now generally preferred wherever a structure is feasible.

In addition to small molecule drug discovery, structural biology is also relevant to deliver insights for structure-based vaccine antigen design and other biologics discovery processes.

KS: How does cryo-EM single particle analysis differ to other forms of cryo-EM?

There are two three-dimensional transmission electron microscopy techniques that are closely related both in terms of image acquisition and processing. One is cryo-EM tomography and the other one is single particle analysis (SPA). Cryo-EM tomography unravels ultrastructure of cellular components and smaller cells whereas cryo-EM SPA is used to determine 3D structures of macromolecules and macromolecular complexes at near atomic resolution. Microcrystal electron diffraction (MicroED) is another cryo-EM technique and is used for the analysis of crystalline samples less than 500 nm thick. It works very similar to X-ray crystallography. The resolution that can be obtained is highest for MicroED, and lowest for tomography.

KS: Why is cryo-EM, and in particular cryo-EM single particle analysis, well suited to drug discovery applications over other structural analysis techniques?

Cryo-EM SPA is used today to complement traditional methods such as X-ray crystallography or nuclear magnetic resonance for structure-based drug discovery. X-ray crystallography has been highly successful in structure enablement of soluble drug target classes like kinases and proteases but has a primary requirement that these proteins need to form crystals. Despite intensive efforts, many protein families including membrane proteins and large soluble assemblies have remained recalcitrant to crystallization.

As an example, though membrane proteins account for over 60% of drug targets, only 2% of existing crystal structures represent membrane proteins, which means the structural information for many such targets of interest to pharma remain unknown. Cryo-EM SPA is the method of choice to address these intractable targets, enabling structural analysis of macromolecules such as ion channels, transporters, receptors and membrane protein complexes. With cryo-EM, it is now commonplace to generate structures at a resolution that can enable the identification of small molecules and ions.

The highest cryo-EM resolution structures are now in the near-atomic to atomic range which makes it easier to unambiguously assign the binding mode of these molecules, aiding hit and lead optimization and developing highly-effective drug candidates for the most challenging drug targets.

KS: How much of a barrier do you think the technical skill required to perform cryo-EM analyses has been in the past for its adoption by more users? How is this situation changing?

The general thinking until recently was that cryo-EM analysis is complicated and a complex technique which requires a high level of expertise and substantial capital investment. With the introduction of the iSPA workflow, we made a big step forward in terms of ease-of-use and are aiming for cryo-EM to be performed by a much broader range of pharma scientists with minimal training. In addition, with the recently introduced cryo-EM access as a service program, we offer various levels of services through partner service centers providing the opportunity to learn the technology from cryo-EM experts and determine the value and potential of cryo-EM on your own samples in a controlled environment. All of these measures are designed to lower the barriers to cryo-EM access for the pharmaceutical industry.

KS: How are recent developments enabling atomic resolution with cryo-EM likely to impact pharmaceutical applications?

Innovative developments as demonstrated by recent publications have pushed the resolution limit of cryo-EM to atomic range with unprecedented structural details that allows the visualization of individual atoms in proteins. While this level of detail may not always be necessary for the structural insights needed to answer some biological questions, it at least shows that resolution is becoming less of a bottleneck for cryo-EM in the visualization of small molecules, lipids and antibodies bound to proteins. This makes cryo-EM an attractive tool to aid the drug discovery process.

With pharmaceutical labs now turning to cryo-EM to uncover the structures of difficult-to-crystalize molecules, they are looking for ways to increase their productivity so they can more quickly move from early drug discovery to clinical trials.

Our recently launched iSPA Workflow is the first complete SPA-dedicated solution specifically designed for the pharmaceutical industry to provide an easy-to-use, highly productive and automation-enhanced solution that lowers the barriers to cryo-EM adoption and accelerates the path to new and more effective drugs. This new cryo-EM solution was developed with input from users in the pharmaceutical industry to support structural biologists of all experience levels from sample vitrification to data collection to deliver faster results, higher resolution and reduce the cost of bringing new drugs to the market.

The Krios Rx cryo-TEM flagship of the iSPA workflow is a SPA-only microscope dedicated to pharma drug discovery process and comes with a powerful combination of innovative features and enhanced automation for unattended data collection to provide the optimal throughput with guaranteed productivity. This innovative cryo-EM solution is ideal for generating de novo and repeat structures of drug targets in combination with their ligands quickly to match the timeline for hit and lead optimization.

As an example, we can now get the structure of apoferritin to near-atomic resolution within 10 minutes of data collection. On a human membrane protein such as the GABA A receptor, we can get a structure of this receptor bound to its drug compound in 3-4 hours to near-atomic resolution. This cryo-EM solution will certainly change the pace of drug discovery!

Raymond Schrijver was speaking to Dr Karen Steward, Science Writer for Technology Networks.