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Biological Chemistry

Drugmakers Tune To New Channels

ACS Meeting News: Medicinal chemists set their sights on sensory ion channels to find pain, cancer, asthma treatments

by Lauren K. Wolf
April 7, 2014 | APPEARED IN VOLUME 92, ISSUE 14

Credit: Yifan Cheng & David Julius Labs/UCSF
When triggered by chemical irritants (spider toxin binding site is purple, resiniferatoxin site is red), TRPV1 opens two sets of doors in its central pore to allow ions through. Each of TRPV1’s four domains is shown in a different color.
Credit: Yifan Cheng & David Julius Labs/UCSF
When triggered by chemical irritants (spider toxin binding site is purple, resiniferatoxin site is red), TRPV1 opens two sets of doors in its central pore to allow ions through. Each of TRPV1’s four domains is shown in a different color.

In some families, brothers and sisters don’t look much alike. They might share the same pointy chin, for instance, but the resemblance ends there. Even their personalities can be like night and day.

This is also true in the world of protein receptors: Despite being related, family members don’t always look or behave similarly. Take the TRP (transient receptor potential) channels. Residing in cell membranes all over the body, this family of ion channels is so diverse genetically, “any two of them might be less than 20% identical to one another,” according to Magdalene M. Moran, vice president of biology at Hydra Biosciences, in Cambridge, Mass.

As a result, the 30 or so members of the TRP family carry out a broad range of tasks in the human body. They’re the reason we feel pain after eating a chili pepper, and they contribute to the itch we feel after a bug bite. They help us sense when a cup of coffee is too hot.

But TRP channels also do far more than sense the environment around us. Genetic mutations in some of the proteins cause conditions as varied as kidney disease, dwarfism, and a disfiguring skin disorder called Olmsted syndrome.

This is quite a disparate family of ion channels, Moran pointed out when speaking at last month’s American Chemical Society national meeting in Dallas. “But the great thing about this diversity is that it should make it easier for us to design therapeutic compounds specific to each channel.”

During a session in the Division of Medicinal Chemistry, Moran came together with academics and other industry scientists to discuss progress in TRP channel drug discovery. The scientists hope to design therapeutics targeted at the TRP family for treating chronic pain, asthma, and eventually, some of the diseases in which defective versions of the channels are involved.

Compared with other protein receptors, the TRP channels are still relatively new, Moran said. The first sodium ion channel was discovered in 1980. But it wasn’t until the late ’90s that a research team cloned a TRP channel with a known function from rodent DNA.

“We were looking for the receptor for capsaicin,” the molecule that gives chili peppers their sting, said David Julius, a biologist at the University of California, San Francisco. His team’s search turned up TRPV1. Soon the entire TRP family began drawing interest from scientists around the globe.

Despite more than 15 years of work and progress, though, today “we really still don’t understand what all of the channels do, in terms of their physiology and what activates them,” Julius told C&EN.

Not understanding how the channels work has deterred some drugmakers from going after the TRP family as a set of therapeutic targets, Moran said. She sees the TRP channels’ newcomer status as an advantage, however. “The chemical space around them is not nearly as mined as it is for other ion channel targets,” she said.

So some firms, including Moran’s, are putting more and more time and money into exploring these receptors. According to a recent survey conducted by ACS’s Chemical Abstracts Service, firms filed about 140 patents for molecules targeted at TRP channels in 2013.

Because little is known about the channels’ three-dimensional structures, scientists are currently identifying compounds that either activate or block the receptors without the aid of computer modeling, Moran explained. “You’re basically looking at an assay and figuring out if your compound binds or not” without knowing exactly where it binds, she added.

Screening methods might become more sophisticated soon, though. At the end of last year, Julius’s lab at UCSF reported the first atomic-resolution structure of a TRP channel—the chili pepper sensor TRPV1 (Nature 2013, DOI: 10.1038/nature12822 and 10.1038/nature12823). “A lot of people have been trying to do this over the past few years,” Julius told C&EN. TRP channels seem to be less rigid than other membrane proteins, he added, so it’s been especially difficult to crystallize them and discern their structures with traditional X-ray crystallography.

Julius’s team was able to nail down the capsaicin receptor’s structure with single-particle cryoelectron microscopy, a method that probes hydrated proteins after they’ve been rapidly frozen onto a grid. The 3.4-Å-resolution structure the researchers obtained reveals that TRPV1 has four identical subunits that stick together to form a central pore. Within the pore are two sets of gates: one near the outside of the cell membrane, and one near the inside. Both have to open for ions to pass through. Like most TRP channels, TRPV1 is nonselective about the ions it admits; calcium, sodium, and the like are given passage.

When capsaicin binds near TRPV1’s inner gate, it forces both barriers to swing open briefly and allow ions through. On nerve cells, this ion flow triggers a series of events that send a pain signal to the brain.

Because TRPV1 is the best characterized member of the TRP family, it’s also the channel on which pharmaceutical firms have focused most of their efforts to date.

Oft-used painkillers such as oxycodone give users relief, but they are addictive, and they make patients drowsy. So a number of drugmakers have been looking to TRPV1-modulating compounds as alternatives. Unfortunately, antagonists of TRPV1—compounds that block the channel—have side effects too.

In addition to sensing capsaicin and inflammatory agents such as spider toxin, TRPV1 responds to heat. Blocking it, firms have learned, triggers an increase in core body temperature. In one extreme case, Amgen reported in 2008 that a patient given the experimental compound AMG517 spiked a fever of almost 104 °F (Pain, DOI: 10.1016/j.pain.2008.01.024). Blocking TRPV1 also puts patients at risk of unintentionally burning themselves. At a 2009 conference, Merck & Co. reported that some subjects dosed with the antagonist MK2295 thought a water bath was lukewarm when it was actually scalding hot.



But all is not lost for TRPV1. A small molecule that activates the channel rather than blocking it has had some clinical success.

Originally derived from a cactuslike plant, resiniferatoxin is an analog of capsaicin with 1,000 times the potency. It binds to TRPV1 and props open the channel’s central pore, flooding nerve cells with ions long enough to kill them.

Credit: Courtesy of Michael Iadarola
Iadarola (from left), Mannes, and former postdoc Laszlo Karai gathered for a photo in October 2009 to commemorate the day they treated their first human patient with resiniferatoxin.
Credit: Courtesy of Michael Iadarola
Iadarola (from left), Mannes, and former postdoc Laszlo Karai gathered for a photo in October 2009 to commemorate the day they treated their first human patient with resiniferatoxin.

When Michael J. Iadarola, a sensory biologist at the National Institutes of Health, first saw this effect in a petri dish, he didn’t necessarily think “painkiller.” But after chatting with anesthesiologist Andrew Mannes in a hallway at NIH around 2000, he changed his mind. Iadarola described resiniferatoxin’s ability to kill TRPV1-expressing nerve cells. Then he mused that injecting the compound near those pain-signaling cells would take them out but that it would also cause a person a lot of pain in the process. Mannes had a solution: “Just knock the patient out.”

After that conversation, Iadarola, Mannes, and others at NIH tested the concept—anesthesia followed by localized resiniferatoxin injection—in rodents and dogs. The results were promising. The dogs they tested had bone cancer; some were in such agony that they had difficulty walking. But after receiving a dose of toxin in a specific region of their spinal cords, the canines were able to amble around again (Anesthesiology2005,103, 1052).

Encouraged, the team took resiniferatoxin into a Phase I clinical trial. The ongoing trial is now being sponsored by San Diego-based Sorrento Therapeutics. Mike Royal, senior vice president of clinical development for Sorrento, told C&EN that preliminary results are positive. One wheelchair-bound patient with pancreatic cancer, for example, was able to get up and walk after his injection. In the future, Iadarola hopes resiniferatoxin can also be used to kill nerve endings in the joints of patients with osteoarthritis.

At the meeting in Dallas, another company disclosed its efforts to design painkillers by targeting a different member of the TRP family. David Pryde, a research fellow in worldwide medicinal chemistry at Pfizer, presented Phase I clinical trial data on the compound PF05105679, which blocks TRPM8. This channel typically responds to cold temperatures and the cooling agent menthol.

When given to subjects in an oral suspension, PF05105679 enabled the participants to hold their hands in a bucket of ice water for a long time before feeling pain. The new compound’s pain-alleviating effects matched those of oxycodone for about one hour after administration.

The TRP channel family has become more popular among academics and industry researchers in the past decade. SOURCE: Chemical Abstracts Service
The TRP channel family has become more popular among academics and industry researchers in the past decade. SOURCE: Chemical Abstracts Service

On the basis of the side effects observed for TRPV1 antagonists, Pfizer kept a close eye on its patients’ core body temperatures after they took the TRPM8 blocker. No changes occurred. Pryde reported that participants experienced only a “hot feeling” in their mouths, akin to eating a chili pepper.

“There’s probably a connection between the cold-sensing channels and the hot-sensing channels,” he explained. “If you block one, you can imbalance the homeostasis between them.”

So far, most of the TRP-targeted compounds that have entered clinical trials have been painkillers. But molecules meant for other conditions aren’t far behind. For example, because prostate tumor cells overexpress TRPM8, Seattle-based biotech firm Dendreon designed an experimental drug to activate the channel and kill the malignant cells on which it resides. The compound, D3263, is currently in a Phase I trial.

Compounds targeted at TRPA1 are in the works too. The “it” channel among pharmaceutical firms at the moment, TRPA1 is activated by a multitude of chemical irritants, including mustard oil. And one of the places it resides is in the nerve endings that line the airways of the lungs. As a result, companies such as Glenmark Pharmaceuticals, in Mumbai, are designing molecules that block the channel to treat asthma and cough.

At the meeting in Dallas, Glaxo­SmithKline also reported drug design efforts targeted at a TRP family member located in the lungs. TRPV4, an ion channel activated by high pressure, dots the cells that line the lungs’ blood vessels.

Mui Cheung, director of medicinal chemistry in GSK’s virtual proof-of-concept discovery performance unit, told the audience that fluid often accumulates in the lungs of patients with heart failure—a condition called pulmonary edema. As pressure builds up in the lungs’ blood vessels, fluid leaks into a person’s airways.

Targeting TRPV4 could offer a solution, Cheung suggested. Because the channel opens in response to pressure, Cheung and her team hypothesized that blocking it could protect blood vessels and prevent fluid leakage. So they designed a compound, GSK2193874, and tested it on rodents experiencing heart failure. The experimental drug both protected the animals from edema and reversed the edema after it began, depending on when they were given the compound (Sci. Transl. Med. 2012, DOI: 10.1126/scitranslmed.3004276).

It’s still too soon to tell whether current TRP channel efforts will be successful. But the general feeling among scientists is that eventually some “really important” drugs will act on the receptors, UCSF’s Julius said. In the meantime, having compounds that block or activate the TRP channels will be vital to understanding how the receptors function, he contended. “Having better chemistry for these channels would be enormously helpful.” 



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