Images captured at near-atomic scale resolution reveal that tiny viruses with their crystal casing are by far the smallest protein crystals ever analyzed. This opens up new opportunities to understand viruses and develop effective drugs. Credit: Ken Goldie, C-CINA Basel

ASU research aims for a future when medicine has no side effects

Researchers at ASU’s Biodesign Center for Applied Structural Discovery are determined to make this scenario a reality.

It’s the harsh give-and-take in the world of medicine: a new drug brings promise for fighting a disease, only to find that side effects compromise therapeutic gains. Imagine, however, a physician confidently prescribing a blood pressure medication or even a cancer drug, knowing with, say, more than 90 percent certainty that the medication will do its job and offer little if anything in the way of side effects.

Petra Fromme, director of ASU’s Biodesign Center for Applied Structural Discovery, leads a team of researchers determined to make this scenario a reality.

The protein/drug connection

Frommes research analyzes the structure of some of the human body’s thousands of membrane proteins that have a role in certain diseases. This information is used to develop more effective drugs that can bind specifically to those protein molecules. When a drug strongly binds to the correct protein, it is extremely unlikely it will bind to another “wrong” protein. As a result, the risk of side effects is reduced and a lower dose is required, causing less liver toxicity, a common problem that is the reason many drugs fail in clinical trials.

However, the majority of the proteins Fromme studies have functions that are not yet known to man because scientists have struggled to get a clear picture of how they work. But that clear picture will soon be available to Fromme and her team of researchers. A game-changing laser technology will soon be installed inside ASU’s currently under construction Building C at the Biodesign Institute. It will provide some of the best visuals to help analyze the structure of these critical proteins.

“If you have the structure of the protein receptor, then you can design the perfect drug for it,” Fromme says.

Freeze framing a protein

For the past decade, huge advancements have been made in XFEL technology, with ASU leading the charge to adapt it for the very first time to look at protein structures. Other researchers said it couldn’t be done, but ASU proved them wrong. Fromme helped develop a method that allows scientists to see what has never been seen before.

In addition, with the help of ASU’s X-ray pioneers, John Spence and Henry Chapman, a new XFEL technology was developed that works like a high-speed camera. Now, scientists can see a molecule in its active state, not just as a static photo.

“You want to get a movie of the molecule binding, for example, to the drug, and all the interactions afterwards. [That] structure of the molecule in action can help you design that perfect drug,” Fromme says.

Last year, Fromme’s team was able to analyze the structure of a protein that regulates blood pressure. Understanding that structure allowed the team to better see how different blood pressure medications could target the molecule. Choosing only the drugs that bind best with that protein can also streamline the “right” drugs to clinical trials.

Currently, only about 5 percent of drugs in clinical trials make it to market, largely due to side effects. Knowing exactly which drugs bind perfectly with the required protein means fewer drugs are needed to go to trial, but the few that do go to trial have a very high likelihood of succeeding.

A challenge, an opportunity

Unfortunately, XFEL technology comes with some considerable limitations. Building one costs more than $1 billion and requires $100 million annually to operate. The lasers are also space hogs; most are about a mile long.

However, William Graves, associate professor in ASU’s physics department and Biodesign Institute, is building the world’s first “compact” XFEL at ASU. It will vastly shrink the costs and footprint of the technology, making it more accessible to scientists and others all over the world. When constructed, it will settle in at a humble 3 feet in length, cost about $10 million to build and $1 million to operate annually. The laser will be available to Fromme and other researchers when the new Biodesign C building is completed in spring 2018.

Having the compact XFEL available to Fromme could be a research game changer. Getting a single day of “beam time” on one of the existing XFELs is highly sought after, with more than 80 percent of the applicants turned away, and costs about $300,000 per experiment.

“We’re looking forward to breaking this (research) logjam,” Graves says.

In many ways, the laser is as much an entrepreneurial venture as it is a research tool. Mark Holl, an ASU research scientist, oversees the new construction of the compact XFEL’s new home on the Tempe campus. He takes input from a multidisciplinary ASU team that will use the compact XFEL. It’s a mix of engineers, biologists, chemists, crystallographers and software programmers, to name just a few.

“This is all done in a very team-science way. It’s academic research, but really it’s like a small startup. It’s very entrepreneurial,” he says.

To learn more about how ASU research impacts the globe, visit the Biodesign Institute website. To contribute to groundbreaking medical research, contact Eric Spicer at eric.spicer@asu.edu or visit GiveTo.asu.edu.
By supporting Campaign ASU 2020, you share your own personal vision for the institution and ensure that the values that have made ASU great continue to guide us for generations to come. For more information please visit https://giveto.asu.edu/

Originally published at www.azcentral.com on February 17, 2017.

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