A Safer Pain Killer Hints at New Possibilities

Nevan Krogan, PhD, Brian Shoichet, PhD, and Mark Von Zastrow, MD, PhD
2016 - 2019 Weill Innovation Award

"I think we may be on the verge of understanding how drugs work at the level of the receptor itself...in a way that we can potentially rationally control or manipulate these drug effects." Mark Von Zastrow, MD, PhD

When asked what he plans to do with the award he shares with Brian Shoichet, PhD, Department of Pharmaceutical Chemistry, and Nevan Krogan, PhD, Department of Cellular Molecular Pharmacology, Mark Von Zastrow, MD, PhD, Department of Psychiatry, has a short, but audacious, answer: “Revolutionize pharmacology.” It’s an unexpected response from an otherwise understated man, but when you consider the basis for this work – an opioid alternative with the potential to relieve pain without the risk of addiction – it suddenly seems like a perfectly reasonable goal.

New ideas about how drugs work: “The old-school idea is essentially that drugs work through a lock-and-key mechanism. The drug receptor is the lock, and the ligand – whether it’s a plant-derived compound used as a drug, like morphine, or a naturally released peptide like encephalin – is the key. If compounds have similar shapes, they can open the same lock but not at the same time. What we’re coming around to is an idea that was considered heretical only a few years ago: that we might be able to unlock a receptor with more than one key and produce different biological effects.” Mark Von Zastrow

Fresh possibilities for therapeutics: “If we’re right – something we hope to find out with our Weill Award – it opens up an entirely new world in pharmacology, because everything we think about how drugs work is based on this potentially flawed lock-and-key model. Now we’re talking about broadly expanding the properties drugs can have, as well as their therapeutic profiles, by virtue of this principle that we don’t yet really understand.” Brian Shoichet

How the project will work: “We want to use this really different chemistry, including the incredible opioid compounds that Brian has developed, to find out if our hypothesis holds up. What I think we may be on the verge of doing is actually being able to understand how drugs work at the level of the receptor itself, and then at the level of the cells in which the receptors are functioning, in a way that we can potentially rationally control or manipulate these drug effects. Until very recently, we didn't have the ability to do any of this, partially because we didn’t have the right compound to test, so it was really just a matter of lucky guesswork.” Mark Von Zastrow

Why they’re working together: “It was a natural connection to think about using these kinds of approaches together with the new chemistry that Brian has discovered as a way of really trying to understand how you can get different properties of these drugs. We've never had a way to get an incisive answer, so we were excited about the possibility that by putting together our expertise and our interests, we could actually take an original shot at it.” Mark Von Zastrow

How long the collaboration has been brewing: “I first came to Mark with a collaboration idea in 2006. When he got done laughing me out of his office, we almost did something then. We've been talking about doing this sort of thing together for almost a decade, but I really think it took having the right compound for the right problem to precipitate the actual project. The award came along at the perfect time and allowed us to capitalize on that momentum.” Brian Shoichet