Powerful tool invented to probe entire human proteome

The technology could give the search for new drugs, especially for cancer and terminal diseases, a significant boost.

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The advent of a new screening method that combines mass spectrometric imaging and microarray technology holds promise for protein-based pharmaceuticals.

The technology can target large sets of human proteins simultaneously, what scientists call ‘massively parallel’ analysis, using a scattergun approach.

Mass spectrometry allows scientists to detect, quantify and distinguish proteins and drugs by composition, down to their smallest atoms. Microarrays can ‘capture’ specific proteins.

The scientists used the combined technique to probe new and existing drug-protein interactions, as well as for drug discovery, since the new tool can simultaneously screen multiple drugs against all protein targets.

“This will not only dramatically accelerate the discovery of new drug targets, but also allow pharmaceutical companies to see how candidate drugs might bind to ‘off-target’ proteins, so they can choose drugs with minimal side-effects,” says Mark Lim, the vice president and chief scientific officer at US lab AmberGen, a spin-off company from the Boston University Photonics Center.

Proteins are vital nutrients and essential components of all cells. They also help maintain cells, dictate their phenotypes and mediate cell signalling. This makes them a key target for drug development.

When proteins over-perform or don’t work, they can trigger pathological changes in cells that lead to medical conditions like cancer. When drugs target them inappropriately, it can cause adverse side-effects.

Previously, researchers have not been able to examine drugs’ interactions with the 100,000-plus proteins in the body – known as the human “proteome” – because the drugs had to be fluorescently labelled in order to be identified. The labelling could alter their interaction with proteins, leading to false results.

Testing methods that didn’t require labelling meant that researchers needed a good idea about the activity of the specific protein and drug under scrutiny, making wide-scale screening difficult. 

Bead-GPS, the test developed by Lim and colleagues, however, uses microscopic beads that attach to both a unique coding agent and specific proteins through “linkers”. Photocleavable linkers create links that can be broken by specific types of UV light and are used to attach coding agents to the microscopic beads. The scientists can detect molecules bound to these beads using mass spectrometry. Proteins are attached to the beads by non-cleavable linkers.

“In the particular type of mass spectrometry used, the light from the instrument’s laser beam breaks the photocleavable linker that attaches the coding agent to the bead so that it may be detected. The drug, which is non-covalently bound to the bead through the protein, is also released by other means,” says Lim.

AmberGen’s test therefore doesn’t influence the drugs’ activity in the way fluorescent labelling would have, allowing researchers to observe how any drug interacts with any number of proteins.

“The potential impact of proteome-wide drug discovery is that one obtains a much more global picture of how drugs might alter the cellular process, thereby allowing detection of potential side-effects at a much earlier stage in the drug discovery process than animal or human testing,” Lim says.

He adds that this new method can also help them “repurpose” existing drugs to treat diseases they haven’t been previously intended for.

The entire process takes place on a single chip, roughly the size of a microscope slide. The researchers studied proteins known as kinases, which play a key role in cancer cell proliferation.

“We anticipate Bead-GPS will have a major impact in oncology, due to the dominance of kinase inhibitors in targeted cancer therapy,” he says. “However, since it will work for all types of protein classes, it is not limited to specific diseases or classes of disease”.

References

  1. Zhou, Y., Liu, Z., Rothschild, K. J., & Lim, M. J. Proteome-wide drug screening using mass spectrometric imaging of bead-arrays. Scientific Reports (2016). | article

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