Cryo-EM Success in Pharma

Want to learn how your drug discovery can benefit from cryo-EM? Learn from your peers’ successes. The benefits of this method have been proven in publications from pharmaceutical companies, showing how cryo-EM delivers previously unattainable structural insights needed to accelerate drug discovery.

The following recent publications provide proof of how cryo-EM delivered critical structural insights in different disease areas for a wide range of drug targets. In several cases, cryo-EM provided the insight that was unattainable with other methods, thus accelerating the path to drug discovery.

Recent cryo-EM publications:

Amgen: Cryo-EM clarifies synergistic activity of anti-tumor antibodies

Cryo-EM structure is vital for the development of potent bispecific antibodies.


Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–30% of breast cancer tumors and is associated with a more aggressive disease, higher recurrence rate, and increased mortality. Trastuzumab and pertuzumab are HER2 receptor blockers and have become the standard of care for the treatment of HER2-positive breast cancer. Adding these monoclonal antibodies to the treatment regimen of HER2-positive breast cancer has changed the paradigm for treatment in that form of cancer. The effectiveness of their synergistic activity has been well validated in research as well as in clinical practice.

Amgen: Cryo-EM clarifies synergistic activity of anti-tumor antibodies
Cryo-EM Structure of HER2-trastuzumab-pertuzumab Complex; Hao Y, Yu X, Bai Y, McBride HJ, Huang X (2019), PLoS ONE 14(5): e0216095, Published: May 1, 2019
Objective
Gain structural insight into the synergistic activity of the ternary complex HER2-trastuzumab-pertuzumab.
Benefits of cryo-EM
Instrumental in gaining better understanding of synergistic activity.
Key insights for the design of bispecific molecules with potentially greater clinical efficacy.
Cryo-EM insights complement X-ray crystallography.

Genentech (Roche): Structural basis of selective sodium channel inhibition

Cryo-EM complements crystallography in unraveling selective sodium channel blockers.


Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Mutations in Nav channel subtypes are associated with migraines, epilepsy, pain, and cardiac and muscle paralysis syndromes. Channel blockers lack subtype selectivity and have not been well understood.

Genentech (Roche): Structural basis of selective sodium channel inhibition
Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin; Xu et al., 2019, Cell 176, 702–715, Published: February 7, 2019
Objective
Determine key structural templates to design selective Nav channel antagonists using spider protoxin-II (ProTx2).
Benefits of cryo-EM
Cryo-EM analysis independently validated the crystallographic structural model of the receptor site.
Crystallographic structure took many years to solve. Soaking in compounds was not successful, so cryo-EM was the ultimate choice.
Cryo-EM structure supports mechanistic interpretation of ProTx2 complex shifting the activation of Nav and pharmacologically stabilizing the closed-channel state.

Novartis: Cryo-EM enables development antibody screen against polyomaviruses

Cryo-EM reveals structure of viral epitope, enabling development of new therapies.

Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Mutations in Nav channel subtypes are associated with migraines, epilepsy, pain, and cardiac and muscle paralysis syndromes. Channel blockers lack subtype selectivity and have not been well understood.

Novartis: Cryo-EM enables development antibody screen against polyomaviruses
Human Memory B Cells Harbor Diverse Cross-Neutralizing Antibodies against BK and JC polyomaviruses; Lindner et al., 2019, Immunity 50, 668–676, 2019, Published: February 26, 2019
Objective
Identify complex binding site of the virus capsid protein, which was not possible with crystallography due to the complex’s quaternary structure.
Benefits to cryo-EM
Cryo-EM reveals the quaternary nature of viral epitope and unravels potent modality for inhibiting polyomavirus infection in kidney transplant recipients and other immunocompromised patients.

Pfizer: Structure of the human frataxin-bound iron-sulfur cluster assembly complex

Cryo-EM provides insight in clinical mutations of Friedreich’s ataxia.


Iron-sulfur clusters (ISC), located in the mitochondria matrix, are five-protein complexes containing the cysteine desulfurase that is activated by frataxin (FXN). Deficiency in FXN leads to Friedreich’s ataxia (FRDA), a genetic neurodegenerative disorder that results in cardiological symptoms, loss of limb sensation, locomotion symptoms, impaired speech, and neurological damage.

Pfizer: Structure of the human frataxin-bound iron-sulfur cluster assembly complex
Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism, Nicholas G. Fox, et al., Nature Communications 10, Article number: 2210 (2019), Published: May 17, 2019
Objective
Determine complex structure to find out how FXN stabilizes ISC; guide FRDA clinical mutations.
Benefits of cryo-EM
Structure of FXN-bound human complex is one of very few reported cryo-EM structures of < 200 kDa and < 3.5 Å resolution for both membrane and soluble proteins.

Cryo-EM is applied here to a clinically-relevant target that remain intractable for X-ray crystallography.

Want to stay informed on cryo-EM publications in Pharma and other interesting cryo-EM news?

Register now

* Required field

*
*
*
*
 
 
 Speak with a cryo-EM expert
 Request a demo
 Get a quote

To ensure that we are complying with your preferences, we need to confirm permission to send you communications by email.

 Please confirm you would like to receive marketing and promotional email messages about Thermo Fisher Scientific products and services.