ChemInteract consortium wins funding to assess chemical toxicity

There are limited approaches for analyzing the specific interactions that occur between the proteins of our cells and the thousands of chemicals that are in everyday use. The relationships between these interactions and the adverse effects that may arise are also often poorly understood. The ChemInteract consortium will build on existing laboratory techniques that are successfully used in pharmaceutical discovery to identify how a drug interacts with a living cell, extending the technology to identify crucial interactions between chemicals and human proteins that could indicate a potential safety concern.

Phenotox founder and toxicologist Dr. James Sidaway explains that the ChemInteract consortium is a collaboration between Phenotox, Retrogenix, Sheffield Hallam University and Instem funded by the NC3Rs CRACK-IT “Targeting Off-targets” competition.

“Retrogenix, Phenotox and Sheffield Hallam University are developing a novel label-free method to assess the binding of chemicals to targets expressed in cell microarrays,” Sidaway tells DDNews. “In parallel, Phenotox and Instem are using their extensive toxicology and cheminformatics expertise to design the ChemInteract cell microarray, which will use the label-free method to detect binding of chemicals to a large panel of membrane and intracellular proteins associated with adverse events.”

“If funding is obtained for the second phase of the project, the consortium intends to fully validate the microarray and develop companion informatics analysis tools to facilitate interpretation and risk assessments of chemical binding data within an adverse outcome pathway context,” Sidaway adds. “This integrated solution will substantially increase screening capacity and knowledge of off-target mediated adverse events for new chemicals, thereby reducing unnecessary animal testing in toxicology studies.”

The consortium will use complex bioinformatics when developing the tool, to assess the likelihood that the chemical-protein interactions discovered will cause unwanted effects in humans or other animals. Hundreds of human proteins that are often implicated in adverse effects will be incorporated, with the ultimate aim of providing the chemical industry with a rapid and safe method for identifying and understanding potential toxicological issues. This would help “bad” chemicals to be discarded at an early stage, avoiding unnecessary animal testing.

The consortium is led by Phenotox, a company specializing in developing animal-free toxicology approaches. Says Sidaway: “There’s a real gap in predicting the adverse events in humans of new chemicals developed by the pharmaceutical, consumer healthcare and agrochemical industries. This is partly because the full set of protein targets that mediate chemical toxicities has not been discovered. Current safety testing approaches rely heavily on animal studies, which do not fully represent the human situation. Our animal-free approach builds on advanced, but established, experimental technology from Retrogenix and Sheffield Hallam University and existing big data and bioinformatics expertise from Instem. We are delighted to receive NC3Rs funding to develop this new platform aimed at substantially enhancing the current safety testing of new chemicals.”

Commenting on the impact of the initiative, Dr. Jim Freeth, managing director of Retrogenix, said: “Our human cell microarray technology has been tremendously successfully in pinpointing the specific protein targets for drugs developed by the global pharmaceutical industry. This project now provides an excellent opportunity to focus in on key toxicology targets which would not only contribute to the development of safe and effective chemicals, but could also be used in pharmaceutical toxicology, reducing the amount of animal testing required by both industries.”

“The elegance of the Retrogenix microarray technology lies in expressing full-length human proteins in the context of human cells. This allows for normal trafficking within the cell, correct folding and natural post-translational modifications. Once expressed in their native state, these proteins are then available to interact with the test molecule—whether this is an orphan ligand or an environmental chemical—providing a more natural environment in which to capture real-life interactions,” Freeth observes.