How Drugs Can Minimize the Side Effects of Chemotherapy

Summary: Researchers have identified the 3D structure of a brain receptor that causes vomiting and nausea as a result of chemotherapy treatments for cancer. The same receptor also plays a critical role in pain perception, migraines and chronic itching.

Source: University of Zurich.

Researchers at the University of Zurich have determined the three-dimensional structure of the receptor that causes nausea and vomiting as a result of cancer chemotherapy. The study explains for the first time why some drugs work particularly well in ameliorating these side effects. The results also provide important insights into how to develop compounds to effectively tackle other disorders.

Most cancer patients who have to undergo chemotherapy treatment worry about the associated side effects, especially nausea and vomiting. The cause of these unpleasant effects is a receptor in the brain which is normally activated by the neurokin 1 receptor. During chemotherapy, this receptor is greatly overstimulated. The same receptor also plays a central role in many other medical problems – such as migraine, perception of pain and pruritus (severe itching).

Ever since the receptor was discovered thirty years ago, teams around the world have worked on finding effective and lasting inhibitors. Until now, though, success was limited: While many compounds showed strong activity in the test tube, only very few of them worked in patients. There was no clear explanation as to why this was the case.

Three-dimensional analysis of the structures explains how they work

A team of researchers at the UZH Department of Biochemistry, led by Prof. Andreas Plueckthun, has now managed to solve this mystery. They examined what the three-dimensional structure of the receptor looked like when two effective drugs – EmendTM; (aprepitant) und AkynzeoTM; (netupitant) – were used. They compared this with the use of an early compound that was only active in the test tube. “We could directly see how the effective drugs altered some parts of the receptor such that the drugs could not easily escape anymore,” explains PhD candidate Jendrik Schoeppe, who carried out the structural analyses. “The earlier compound fit just as well onto the receptor but could still quickly leave it.”

a multi colored brain
Most cancer patients who have to undergo chemotherapy treatment worry about the associated side effects, especially nausea and vomiting. The cause of these unpleasant effects is a receptor in the brain which is normally activated by the neurokin 1 receptor. NeuroscienceNews.com image is in the public domain.

New solutions for other medical problems

This study helped the biochemists to exactly determine which chemical structures of the drugs enable a long-lasting attachment to the receptor and thus a durable effect. “This result provides important insights on how to make such highly potent compounds in the future,” says Plueckthun. Until now, a multitude of other disorders influenced by this receptor (though other receptors also play a role), such as migraine, asthma and gastrointestinal disorders, as well as inflammation and depression, could not yet be tackled with efficient treatments. “The detailed understanding of the receptor structure and inhibition mechanism may now give this research a new boost,” hopes Plueckthun.

A better understanding of the long-term effects

The researchers believe that their findings may also be useful in the search for compounds that could be effective on other receptors. The direct comparison of the different drugs binding to the same receptor also gives important clues about what general features define a long-acting clinically successful drug. “We could only find this out because we could directly see the structure in such high detail, and this in turn only became possible through the directed evolution and protein engineering methods we have developed over the last few years,” explains Andreas Plueckthun. “This was a long-term investment that paid off.”

About this neuroscience research article

Funding: Swiss National Science Foundation, German Academy of Science (Leopoldina), European Union, (Heptares and Heptares Therapeutics Zurich) funded the study.

Source: Andreas Plueckthun – University of Zurich
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research for “Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists” by Jendrik Schöppe, Janosch Ehrenmann, Christoph Klenk, Prakash Rucktooa, Marco Schütz, Andrew S. Doré & Andreas Plückthun in Nature Communications. Published January 3 2019.
doi:10.1038/s41467-018-07939-8

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]University of Zurich “How Drugs Can Minimize the Side Effects of Chemotherapy.” NeuroscienceNews. NeuroscienceNews, 10 January 2019.
<https://neurosciencenews.com/cancer-chemo-effects-10488/>.[/cbtab][cbtab title=”APA”]University of Zurich(2019, January 10). How Drugs Can Minimize the Side Effects of Chemotherapy. NeuroscienceNews. Retrieved January 10, 2019 from https://neurosciencenews.com/cancer-chemo-effects-10488/[/cbtab][cbtab title=”Chicago”]University of Zurich “How Drugs Can Minimize the Side Effects of Chemotherapy.” https://neurosciencenews.com/cancer-chemo-effects-10488/ (accessed January 10, 2019).[/cbtab][/cbtabs]


Abstract

Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists

Neurokinins (or tachykinins) are peptides that modulate a wide variety of human physiology through the neurokinin G protein-coupled receptor family, implicated in a diverse array of pathological processes. Here we report high-resolution crystal structures of the human NK1 receptor (NK1R) bound to two small-molecule antagonist therapeutics – aprepitant and netupitant and the progenitor antagonist CP-99,994. The structures reveal the detailed interactions between clinically approved antagonists and NK1R, which induce a distinct receptor conformation resulting in an interhelical hydrogen-bond network that cross-links the extracellular ends of helices V and VI. Furthermore, the high-resolution details of NK1R bound to netupitant establish a structural rationale for the lack of basal activity in NK1R. Taken together, these co-structures provide a comprehensive structural basis of NK1R antagonism and will facilitate the design of new therapeutics targeting the neurokinin receptor family.

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