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A ‘crystal’ clear look at CCR2
February 2017
by Kelsey Kaustinen  |  Email the author
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SAN DIEGO—CC chemokine receptor 2 (CCR2), a protein found on the surface of immune cells, has been a target of interest to scientists for years due to its role in inflammation response. The protein and other associated signaling molecules impact several inflammatory and neurodegenerative diseases, including multiple sclerosis, asthma, diabetic nephropathy and cancer.
 
Despite ongoing efforts, however, there’s been no luck in drug development targeting CCR2, due in part to its unique placement—it spans the membrane of immune cells, with part of the receptor extending outside of the cell and part of it within the cell. When chemokines, inflammatory molecules, bind to the external part of CCR2, the receptor carries the signal into the interior of the cell, where CCR2 changes shape and binds other communication molecules such as G proteins. This kicks off a wave of activity, and the immune cells follow chemokine trails to wherever they are needed in the body.
 
But new information about CCR2 and how molecules bind to it, courtesy of a team at the University of California, San Diego (UC San Diego) could give scientists a better understanding of what is needed to successfully inhibit CCR2.
 
The study in question was published in Nature, and was led by Dr. Tracy Handel, professor in UC San Diego’s Skaggs School of Pharmacy, and Dr. Irina Kufareva, project scientist at Skaggs School of Pharmacy, with Dr. Yi Zheng, postdoctoral researcher also at the Skaggs School of Pharmacy, as first author.
 
Handel noted in a press release that “So far drugs that target CCR2 have consistently failed in clinical trials. One of the biggest challenges is that, to work therapeutically, CCR2 needs to be turned ‘off’ and stay off completely, all of the time. We can’t afford ups and downs in its activity. To be effective, any small-molecule drug that inhibits CCR2 would have to bind the receptor tightly and stay there, and that’s difficult to do.”
 
The Skaggs team was able to determine the 3D structure of the protein when bound to two inhibitors—one at either end—thanks to X-ray crystallography.
 
The team found that the two small molecules turn the receptor “off” by different, mutually reinforcing mechanisms—one binds the external end of the receptor and blocks chemokine binding that would turn the receptor “on,” while the other binds the interior end, where the G protein usually binds, thereby blocking inflammatory signal transmission. Handel noted that this is the first time the internal binding site has been seen.
 
“Receptors that cross the cell membrane are notoriously hard to crystallize. To promote crystallization, we needed to alter the amino acid sequence of CCR2 to make the receptor molecules assemble in an orderly fashion. Otherwise, when taken out of the cell membrane, they tend to randomly clump together,” explained Kufareva.
 
Kufareva tells DDNews that immune system targets like chemokine receptors pose a significant challenge in terms of residence time (how long a compound stays on a receptor) and proper binding, “because where in other diseases you may have target occupancy of maybe 75 percent, and that is sufficient to achieve therapeutic endpoint, with chemokine receptors you need them inhibited at, say, 95 percent at all times.”
 
Another difficulty in targeting these kinds of receptors is the redundancy of the chemokine system, Handel adds.
 
“On a given cell, there might be multiple different chemokine receptors, and many receptors bind multiple chemokines and vice-versa, so that’s always an issue,” she reports. “If you compare chemokine receptors, including CCR2, to other GPCRs, which are considered highly druggable targets, the binding pockets of these receptors are very, very large and open, and that makes making drugs that would have long residence time and favorable properties more challenging. But I think with the discovery of these allosteric binding pockets, there’s other alternatives, and as we get more structural biology that teaches us how we can deal with those types of challenging receptor interfaces, those challenges can be met.”
 
Kufareva points out that the while there are compounds that can target these sites with high potency, there is a trade-off.
 
“This high potency and probably longer residence time is also achieved at the expense of increasing the size of the molecule and deterioration of pharmacokinetic properties like metabolic stability,” she says. “So it is very hard to balance high levels of inhibition of chemokine receptors with all the pharmacokinetic properties of a compound at once.”
 
Handel tells DDNews that moving forward, they hope to work with companies to explore issues like CCR2’s residence time, as well as the potential of polypharmacology, inhibiting more than one receptor at a time, to tackle the issue of redundancy.
 
Code: E021706

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