Imaging anti-sickness drugs at work

A class of drugs called “setrons”, one of the best known of which is “ondansetron”, are potent anti-nausea agents often used in patients with disabling sickness during, for instance, cancer chemotherapy or radiotherapy. This leads to higher than normal blood levels of the signalling molecule serotonin, which can activate a region in the brainstem that triggers vomiting. The setron drug family block one class of serotonin receptors to stop this happening. But their interaction with this receptor has never been visualised directly - it had only ever been inferred. This means we don’t know if we could make modified setron molecules that would work even better. So Sudha Chakrapani, from Case Western Reserve University, set out to capture detailed images, under the electron microscope, of this happening, as she told Chris Smith…

Sudha——基于setron的化学性质s, it was known that it is likely to bind in the same pocket as that of serotonin. And there were indirect studies that showed that it is likely to bind because you make certain perturbations to that pocket, it also not only affects serotonin binding, it also affects setron binding. So these were all indirect indications that setrons binding in the pocket, but it was not shown experimentally. So why this is important is because even subtle changes to the setron molecule can have a huge impact on the efficacy of the drug or the effectiveness of the drug. So this was the information that was not available before the study.

Chris - What did you do then to turn what was indirect evidence into direct visualisation of when these drug molecules go in, where they bind to and how they exert their effect?

Sudha - We used an approach called cryo-electron microscopy. We isolated the receptor. We picked out individual particles and we aligned them and we created a three-dimensional reconstruction of this molecule. And we did this in the absence of setrons and the presence of serotonin, and in the presence of different types of setrons. So we were able to identify the interaction fingerprint, as you may say, between the drug and the receptor.

Chris - So you're literally able to see the molecules themselves and what the molecule looks like when serotonin's in there, when the drugs in there, when nothing's in there, and you can see how the shape of the molecule can be distorted or changed when those interactions occur.

Sudha - Exactly.

Chris - The crucial question of course must be that when you do this and you can really see for real what was happening when the drug was present, does the direct visualisation tie-up with the indirect evidence of how you thought these drugs were working and what did you learn?

Sudha——是的,这个发现reed very well with what we knew from findings in the past. And there were a few surprises. We were able to identify certain setron orientations, which ended up being slightly different from what we had predicted in the past. And we were also able to rationalise what could have been the causes for this discrepancy between past findings and what we're finding right now.

Chris - And is that the crucial step that will then enable us to optimise those drugs going forward?

Sudha - Yes, absolutely. Having a much better idea about the basis for the drug-receptor interactions will definitely pave the way for using this information to design better drugs.

Chris - Obviously when we tweak any drug or we try to make a drug, we have to be very cautious about off-target effects. Is there a danger based on your knowledge of these sorts of receptors and these sorts of drugs that in trying to optimise the drug better for that particular receptor, we might end up making it bind better elsewhere as well, and therefore causing more side effects?

Sudha - Absolutely. This is a danger when we try to modify the drug and actually we are only looking at one target at a given time. So we have to tread very carefully. One way is there are many different types of serotonin receptors that are present in the body. They differ in their location, let's say in the brain versus in the gut. So it is important to understand the functioning of each of these types of receptors and a detailed knowledge of those will allow us to eventually design drugs that are specific for one type versus the other.