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Hormone receptors make tempting drug targets

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Joseph Gingell undertook part of this project to obtain his BSc (Honours); Richard Bailey is a senior research technician; Joshua Bradley undertook a summer project involving this research and was funded by a Pacific Health summer scholarship and mentored by Debbie Hay through his medical degree via the HRC Pacific Health Workforce mentoring scheme; and Tao Qi was supported for her PhD research by this project, recently completing her thesis.

Understanding how a hormone implicated in migraines triggers a response in receptors in the brain could provide a key to developing better drugs for the debilitating condition.

Dr Debbie Hay from the School of Biological Sciences at The University of Auckland says her three year HRC funded project focused on the calcitonin family of peptide hormones which also have relevance to other health issues ranging from diabetes to bone diseases.

Each type of hormone acts on its own specific cell surface receptor. These are the cellular sensors for these hormones and effectively control hormone action. Therefore, by adjusting the activity of these receptors it is possible to mimic or hinder the activity of these hormones and successfully treat disease.

Targeting the receptors has its challenges because the hormones themselves can’t easily be given as drugs because they are rapidly broken down in the blood.

Dr Hay says what they need to do is either develop better analogs of these hormones or come up with molecules that can mimic or block their actions.

“The aim of my research is to essentially create a blueprint of the receptor and how those hormones specifically interact, so that we can learn how large a drug might need to be, exactly where in the receptor it might bind, and to drive new drug discovery programmes.

“You can think of this as, deciphering the receptor code for new medicines.”

Drug development can be done in a number of ways, Dr Hay explains: “You can go for the holy grail of an orally bio-available small molecule, which is difficult to obtain, or you can play with the hormone itself to try and improve its pharmacokinetics and bioavailability.”

She is working with more than one hormone and one receptor – but in the case of migraine the receptor is for a neuropeptide hormone called calcitonin gene-related peptide (CGRP).

“We don’t know why, but this hormone has increased concentrations in the blood when people have a migraine headache and if you give someone this hormone they can develop a migraine,” she says.

“Over the past 18-20 years researchers have been trying to develop new drugs to block the actions of CGRP at its receptors to treat migraine and some of my research was related to that.

“We identified specific contact points in the receptor for some first generation drugs which will hopefully soon reach the market and help develop second and third generation drugs that are more specific and have fewer side-effects.”

The project has progressed well. Her PhD student has finished her thesis and they were able to publish plenty of new findings from their HRC funded work.

Dr Hay has also developed new collaborations with the pharmaceutical company Merck to aid in the development of their migraine compounds, so overall it was a very successful project.

She will continue her migraine work and expand into actually understanding how specific neurons sense this hormone CGRP and signal pain.

“This kind of basic biomedical research is really crucial to the development of future drugs.

“The research just with this family of hormones is relevant to diabetes, obesity, bone diseases, cardiovascular disease and lymphatic insufficiency. So whilst we’re only focused on one particular aspect here there are many other possible outcomes that might arise from this research.