Design of a challenging drug target

Scala’s technology stabilizes a dynamic target to accelerate drug discovery

In collaboration with:

Why it matters

Structural information on protein targets is a cornerstone of drug development because it enables researchers to study how potential medicines interact with their targets and to refine those compounds effectively. Boehringer Ingelheim’s structural biology group had struggled for years with a highly dynamic target that could only be expressed in insect cells, where yields were too low for structural analysis.

Problem

The wild-type protein expressed only in insect cells at insufficient yield, preventing crystallography or cryo-EM and stalling drug discovery.

What was done

Scala designed 50 variants, each carrying 10–41 mutations, and provided them to Boehringer Ingelheim. The company experimentally evaluated the designs for bacterial expression and protein quality.

Results

• Expression: up to 150-fold increased expression compared to wild type

• Thermal stability: 8–12 °C increase in Tm

• Activity: retained in the stabilized variants at levels compared to wild type

• Crystallization: two selected Scala designs crystallized overnight

Impact

The project enabled Boehringer Ingelheim to produce and study a target that had been inaccessible for years. With sufficient material for analysis, structural biology could proceed, providing the foundation for downstream small-molecule discovery. By removing a critical bottleneck and delivering stable, well-behaved protein variants, Scala’s designs saved the company months of work and exemplify how this capability can directly accelerate drug discovery efforts.

Data highlights

~80% of the 50 designs tested expressed successfully in E. coli (gel showing first 16 designs)

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References

Internal collaboration data; partner experimental results.