New understanding of cellular signaling could help design better drugs, Stanford study finds

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An effective drug with minimal side effects — the dream of all drug companies, physicians and patients. But is it an impossible dream?

Perhaps not, in light of new research led by Ron Dror, PhD, an associate professor of computer science at Stanford. IN collaboration with other researchers, Dror used computer simulations and lab experiments to better understand G-protein-coupled receptors, which are critical to drug development.

G-protein-coupled receptors (GPCRs) are involved in an incredible array of physiological processes in the human body, including vision, taste, smell, mood regulation and pain, to name just a few. As a result, GPCRs are the primary target for drugs — about 34 percent of all prescription pharmaceuticals currently on the market target them. Unfortunately, despite all of this drug research, many of the underlying mechanisms of how GPCRs function are still unclear.

We do know that GPCRs act like an inbox for biochemical messages, which alert the cells that nutrients are nearby or communicate information sent by other cells. These messages symbolize a variety of signaling or pharmaceutical molecules. When one of these molecules binds to a GPCR, the GPCR changes shape — triggering many molecular changes within the cell.

Dror’s team investigated the relationship between these GPCRs and a key family of molecules inside cells called arrestins, which can be activated by GPCRs and can lead to unanticipated side effects from medications. Specifically, they sought to understand how GPCRs activate arrestin, so they can use this knowledge in the future to design drugs with fewer side effects.

“We want the good without the bad — more effective drugs with fewer dangerous side effects,” Dror said in a recent Stanford news release. “For GPCRs, that often boils down to whether or not the drug causes the GPCR to stimulate arrestin.”

Researchers know that GPCR is composed of a long tail and a rounder core, which bind to distinct locations on the arrestin molecule. Based on past studies, it was believed that only the receptor’s tail activated the arrestin — causing it to change shape and begin signaling other molecules on its own.

However, Dror’s new study demonstrated that either the tail or core can activate arrestin, as recently reported in Nature. And the core and tail together can activate the arrestin even more, Dror said.

Using this new understanding, the researchers hope in the future to design drugs that activate arrestin in a more selective way to reduce drug side effects.

Dror concluded in the release:

“These behaviors are critical to drug effects, and this should help us in the next phase of our research as we try to learn more about the interplay of GPCRs and arrestins, and potentially, new drugs.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

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Stanford chemists produce chemical — originally from marine creature — needed for new drugs

Photo by Fitzgerald Marine Reserve Docent

One person’s weed is another’s flower. A good example of this is spiral-tufted bryozoan, an invasive marine organism that fouls up marine environments. Although considered a pest by many, spiral-tufted bryozoan is much sought after by researchers since it can produce biostatin 1 — a chemical critical to the development of promising new drugs to treat HIV/AIDS, Alzheimer’s disease and cancer.

Although this bryozoan is abundant, bryostatin 1 is very scarce because it’s difficult to harvest from the sea creature and complex to synthesize. In fact, the National Cancer Institute’s stock of bryostatin 1 is nearly depleted from supplying over 40 clinical trials. So Stanford chemists have developed a new, easier way to synthesize bryostatin 1, as recently reported in Science.

Paul Wender, PhD, a professor of chemistry and of chemical and systems biology at Stanford, has been working for years to develop bryostatin analogs that are more effective for drug development. However, the dwindling supply of bryostatin 1 inspired him to synthesize the drug itself.

“Ordinarily, we’re in the business of making chemicals that are better than the natural products,” Wender said in a recent Stanford news release. “But when we started to realize that clinical trials a lot of people were thinking about were not being done because they didn’t have enough material, we decided, ‘That’s it, we’re going to roll up our sleeves and make bryostatin because it is now in demand.’”

The researchers devised a much simpler synthesize process, cutting the steps down from 57 to 29. They also dramatically increased the yield, making it tens of thousands of times more efficient than extracting bryostatin from spiral-tufted bryozoan and significantly more efficient than the previous synthetic approaches. And they confirmed with a wide range of tests that their synthetic bryostatin was identical to a natural sample supplied by NCI.

So far, the team has produced over two grams of bryostatin 1, and a single gram can treat about 1000 cancer patients or 2000 Alzheimer’s patients, according to their paper. After scaling up production, they expect manufacturers to produce about 20 grams per year to meet clinical and research needs, Wender said in the news release.

They also expect their work could facilitate research using bryostatin analogs derived from their synthesis process. The paper explains that these analogs “are proving to be more effective and better tolerated in comparative studies with cells, disease models in animals, and ex vivo samples taken from HIV-positive patients.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

SPARKing a global movement

browser-98386_1280Many academic researchers are tenacious, spending years in the lab studying the processes that lead to human diseases in hopes of developing treatments. But they often underestimate how difficult it is to translate their successful discovery into a drug that will be used in the clinic.

That’s why Daria Mochly-Rosen, PhD, founded SPARK, a hands-on training program that helps scientists move their discoveries from bench to bedside. SPARK depends on a unique partnership between university and industry experts and executives to provide the necessary education and mentorship to her academic colleagues.

In recent years, Stanford’s program has sparked identical programs throughout the world; at TEDMED 2015, Mochly-Rosen described this globalization. I recently spoke with her about the SPARK Global program, which she co-directs with Kevin Grimes, MD, MBA.

How has SPARK inspired similar programs throughout the world?

We’ve found our solution for translational research to be particularly powerful. Of the 73 completed projects at Stanford, 60 percent entered clinical trials and/or were licensed by a company. That’s a very high accumulative success rate. So I think it has showed other groups that we have a formula that really works – a true partnership with academia and industry. It’s the combination of industry people coming every week to advise us and share lessons learned and our out-of-the-box, risk-taking academic ideas that makes SPARK so successful.

We feel that what we’ve learned is applicable to others. Kevin and I also feel very strongly that universities need to take responsibility to make sure inventions are benefitting patients. So we’re trying to do our part.

How do you and Dr. Grimes help develop the global programs?

When a university asks about our program, we invite them to come visit us for a couple of days so they can talk to SPARKees (SPARK participants), meet SPARK advisors and watch our weekly meeting. Sometimes they also ask Kevin and I to come to their country to help set up a big event or assist in other ways. If they begin a translational research program at their institution, we offer for them to be affiliated with SPARK Global. Everyone is invited.

There are now SPARK programs throughout the world, including the United States, Taiwan, Japan, Singapore, South Korea, Australia, Germany and Brazil. We are also working with other countries, including Norway, Israel, Netherlands, Poland and Finland to help them start a program.

Do researchers in other countries face the same challenges as those in the US when developing new drugs?

There are many common challenges. And there are also some advantages and challenges that are different in other places. So it’s a mix, both within and outside the US.

There are several key components to the success of translation research. It’s important to have a good idea. It’s even more important to have good advisors from industry to help develop the idea. And it’s very important that the people involved are open-minded and are not inhibited by hierarchical structures. In some places, there is a big problem with hierarchy – particularly in parts of Europe and East Asia. In some cultures, it’s also difficult to get experts to volunteer and academics can’t afford to pay multiple advisors. Also, some universities don’t have a good office of technology to help with patent licensing, which can be a major challenge.

You recent held the first International SPARK conference. Do you have future events planned?

The first international SPARK conference was held last summer in Taiwan. We only invited those with an existing SPARK program, because it was an organizational meeting. We spent a lot of time discussing what we want to do together.

The next SPARK Global meeting will be open to every university and will be held at Stanford this fall. There will be half a day for those thinking about starting a new SPARK program at their institution, and then one-and-a-half days for those already involved. We’ll celebrate SPARK’s 10-year anniversary and the formation of SPARK Global. Our overall agenda is to continue to promote SPARK-like programs in universities, as well as come up with ideas that the global network can work on together.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.