Detecting tiny changes using biosensors – The Nano Argovia project NanoGhip is developing a prototype of a biochip for drug discovery

On a chip measuring approximately 10 x 10 mm (gold square), tiny artificial vesicles with integrated protein complexes are placed in four small channels (volume: 0.06 µl). Then, biosensors are used to observe how various test substances affect the protein complexes. The data provides information about the biological properties of the test substances, ultimately allowing researchers to draw conclusions regarding the efficacy and safety of the potential active pharmaceutical ingredients they are studying (Image: InterAx Biotech/Biozentrum).

In the Nano Argovia project NanoGhip, an interdisciplinary team led by Dr. Martin Ostermaier from InterAx Biotech AG (Villigen, AG) is investigating a new screening method for active substances that could lead to the discovery of new medicines. The scientists aim to develop a new type of biochip that analyzes how the chemical and biological molecules in question react with protein complexes in real time. Even at this early stage, it could also provide information about the safety profile of the tested compounds.

Relaying signals
Membrane proteins play an important role in our cells. As well as being fundamental for our survival, they are involved in the development and treatment of diseases. In this context, G protein–coupled (GCP) receptors are particularly significant. Among other functions, they relay signals to the cell’s interior and thereby regulate a whole cascade of vital reactions. In doing so, many of these G protein–coupled receptors interact with a wide range of proteins to form protein complexes.

Searching for new active substances that influence these receptors is difficult because, instead of analyzing one individual protein, it is important to consider entire protein complexes in order to replicate the natural conditions in the cell as closely as possible. Given that these protein complexes are anchored within membranes in their natural environment, they must also be integrated into membranes for the screening process.

Tiny changes
In order to create a biochip, the researchers in the NanoGhip project incorporate natural protein complexes into synthetic membranes. These have very similar properties to the natural membranes but surpass their natural counterparts in terms of robustness. The researchers then use biosensors to monitor structural changes in the protein complexes when test substances come into contact with the system. These tiny conformational changes of the G protein–coupled receptors have a magnitude of just 0.1 to 1.4 nanometers. Using the protein-based biosensors, the scientists derive information about whether a test substance prevents the GPC receptors from relaying signals to the cell’s interior.

The Nano Argovia project NanoGhip is a close collaboration by scientists from InterAx (a start-up of the Paul Scherrer Institute and ETH Zurich), the Paul Scherrer Institute, and the Department of Chemistry and Biozentrum at the University of Basel, with each of them contributing their own very different areas of expertise. “In this project, we’ve brought together a unique combination of experts that allows us to exploit synergies and explore a new approach to the biological screening of substances on a chip,” summarizes project leader Martin Ostermaier.