Simone Weyand, Imperial College London
Simone - Yes so I work on different proteins which are all membrane proteins and the latest result is the histamine receptor and the histamine H1 receptor is a protein which is specifically recognising histamine and histamine is a compound that is involved in our local immune response. So as part of our immune response to foreign objects such as pollen or pet hair or whatever, food for instance, histamine is produced in our bodies. Now binding to the H1 receptor histamine is able to trigger the inflammation response associated with allergic reactions such as hayfever, food and pet allergies.
Meera - So you were looking at the histamine H1 receptor, whereabouts is this particular receptor found, what cells is it on and what role does it play?
Simone - The receptor is found in all sorts of tissues, human tissue, well mammalian tissue essentially. Histamine is a substance that is produced by our bodies and we also have this receptor recognising this histamine in our bodies. So in principle, allergy is basically a hypersensitivity of our immune system
Meera - So hayfever and allergies to things in the environment cause histamine production which then comes and binds to this receptor, is that right?
Simone - Exactly!
Meera - Youíve been looking at the structure of the actual receptor, why is it important to know this structure and what was known about it before and what have you now been able to see that was new?
Simone - There was not a lot known before about this receptor. In biochemical terms, yes, but not how it looks like exactly and for us it was really very important to have a high resolution picture of how this protein looks like and especially what we show is this receptor binding antihistamine drug to it. What we actually could show is a high resolutions picture of this complex and what it means essentially is now the Pharma(ceutical) companies can produce a highly specific drug which is treating or getting rid of the allergies. These drugs are not really specific against this receptor. For instance, heart receptors, receptors for proteins in the heart, like the potassium channel and we can therefore have problems with the heart like arrhythmia, dry mouth or drowsiness, sickness, all these kind of things.
Meera - So how do current antihistamines work then? Do they bind to this histamine receptor and therefore stop histamine binding to it?
Simone - Exactly, that is what happens. So the antihistaminic drugs, they bind to the receptor and block it from histamine binding to it.
Meera - Knowing then the structure of the receptor, how could you make then, or potentially think about designing a drug that would attach to the receptor better? What could you now do knowing this structure and knowing what happens when the antihistamine binds?
Simone - Because we have really the atomic detail of how this structure, the binding site, the active site of this protein reacts with histamine or drug molecules, how it looks like in the smallest detail, atomic detail, the Pharma industry can really specifically design a drug which is only binding to this receptor. We could really see the interaction, the specific interactions of the drug molecule doxypene which is an antihistamine drug available on the market and by comparing this protein, this receptor, with other receptors of known structure we then can also see what other differences, what is important in this environment for the selectivity of the drug molecules etc.
Meera - So youíve been able to see how antihistamines bind to the receptor, what will the next steps be to make a better drug, think about designing a better, more targeted drug?
Simone - For designing a highly selective drug really it now over to the Pharma companies but what they will probably do is design a whole library of drugs which is only interacting with the residues of the active site of this receptor, then screen it probably in animal models to see if itís highly specific, does in interact with other receptors, other proteins, do side effects occur or not and make it really specific enough and reduce it.
For me, or for us, one of the next steps will probably be to see how different antihistaminic drugs available on the market bind to this receptor to see what are the interactions there, what is the difference for the drug that is bound currently and are there some interactions that we didnít see so far, are there more interactions or less interactions. All these differences they have a big influence on designing a highly selective drug against allergies.