Scientists have finally determined the three-dimensional structure of the receptor that causes nausea and vomiting as a result of cancer chemotherapy. In a recent study, they explain why some drugs work particularly well in ameliorating these adverse effects and how future medication can be improved.
Most patients that have to undergo cytostatic treatment dread having to deal with its associated side effects, in particular, nausea and vomiting. Now we know they are caused by a receptor in the brain normally activated by the neurokin 1 receptor, which gets overstimulated during chemotherapy. The same receptor is responsible for inducing other medical problems, such as migraines, the perception of pain and pruritus (severe itching).
Led by Prof. Andreas Plückthun, the University of Zurich research team examined the structure of the receptor under the effect of two drugs, Emen (aprepitant) and Akynze (netupitant). Comparing this to earlier images of the compound, they noticed how the receptor was then altered.
This allowed biochemists to establish which chemical structures of the drugs enable a long-lasting attachment to the receptor and thus a durable effect. Until now, a number of serious conditions influenced by this receptor, such as a migraine, asthma and gastrointestinal disorders, as well as inflammation and depression, could not be addressed with efficient treatments.
“The detailed understanding of the receptor structure and inhibition mechanism may now give this research a new boost”, noted Plückthun.
These findings could also help search for compounds that could be effective on other receptors. Additionally, it could provide insight into ways of creating more long-lasting clinical drugs.
“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”, explained Andreas Plückthun. “This was a long-term investment that paid off”.
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