New study brings medicine closer to non-addictive painkillers

February 27, 2015

Powerful opiate drugs are a mainstay in modern medicine, alleviating pain in both acute and chronic forms. These charms however, bear a curse. Users quickly develop tolerance to their effects, requiring ever-increasing doses of the drug. Further, such opioid compounds lead to drug dependence, owing to their notoriously addictive qualities.

In a first-of-its-kind study, Petra Fromme, a researcher at Arizona State University’s Biodesign Institute, joins an international team using techniques of X-ray crystallography with high-speed lasers to home in on the detailed structure of opioid receptors and synthetic drugs that bind to these sites. Petra Fromme Download Full Image

Their efforts pave the way for the development of powerful new analgesics, capable of blocking pain without generating tolerance or dependency. Their research findings appear in the current issue of the journal Nature Structural and Molecular Biology.

The international research group was led by Gustavo Fenalti (formerly of the Scripps Research Institute, now with Celgene Corporation, San Diego, California) and includes researchers from the laboratory of Raymond C. Stevens with the University of Southern California, as well as members of the SLAC National Accelerator Laboratory; Center for Free Electron Laser Science; Deutsches Elektronen-Synchrotron (DESY)-Hamburg, Germany; and others.

Fromme, director of the Biodesign Institute’s newly established Center for Applied Structural Discovery, highlights the importance of the present study: “Serial femtosecond crystallography permits detailed examination of vital biochemical details that have long eluded proper study. In this case, revealing the subtle interaction of a human opioid receptor with a binding peptide is a critical step for understanding the pharmacological profile of opioid drugs. The research opens the door to a new generation of improved treatments for pain.”

Ancient friend and foe

Opioids figure among the oldest known drugs, their therapeutic uses dating to prehistory. Such compounds are structurally similar to morphine and other natural alkaloid derivatives of the opium poppy. They work by binding to various opiate receptors, located primarily in the central and peripheral nervous systems and the gastrointestinal tract. While this much is known, many mysteries remain regarding their precise mode of action (and their troublesome side-effects).

Opioid receptors belong to a large protein family known as G protein-linked receptors. These sensing molecules outside of cells trigger a cascade of cellular responses that affect the brain.

When an opioid binding agent, called a ligand, binds with a receptor, the result is a dramatic attenuation of pain, often accompanied by a sense of intense euphoria, (a fact accounting for the popularity of opioid drugs, including opium and heroin, for recreational use and abuse).

Fromme’s group has a led a major initiative to better understand this protein family using a powerful new X-ray laser technology.

Three primary opioid receptors are known to bind with various naturally-occurring opioids produced by the body. A more thorough understanding of these naturally-occurring opioids and their receptors is essential for drug discovery of new pain analgesics with more desirable properties.

Researchers hope to create synthetic opiate ligands, capitalizing on their powerful analgesic properties while reducing or eliminating side-effects. The current study examines a particular opioid ligand which has already shown considerable promise as a tolerance-free, dependence-free analgesic.

X-ray vision

X-ray crystallography has been a vital tool for revealing the structure and function of a wide variety of biological molecules, including drugs, vitamins, proteins and nucleic acids, such as DNA. The technique remains a primary method for characterizing the atomic structure of new materials and their properties – key ingredients in the eventual design and validation of new pharmaceutical drugs.

One shortcoming of traditional X-ray crystallography is that X-rays can damage or destroy the delicate crystal structures under investigation. The current study used a pathbreaking method known as serial femtosecond crystallography using a device known as an X-ray Free Electron Laser (XFEL).

The use of XFEL allows much smaller crystals to be used, capturing critical structural information before the sample is destroyed.

In the current study, the team used serial femtosecond crystallography to observe peptide-receptor interactions essential for developing a complete pharmacological profile of opioid peptides, and development and refinement of improved analgesic drugs.

The XFEL method provided unprecedented structural details revealing new molecular determinants of peptide interaction and identifying a key structure contributing to a particular ligand’s activity.

Analysis of that ligand presents a platform for the examination of numerous peptides with pharmacological properties, including new ligands for the management of pain.

In addition to her appointment at the Biodesign Institute, Fromme is a professor at ASU’s Department of Chemistry and Biochemistry.

Richard Harth

Science writer, Biodesign Institute at ASU


William Reber to retire as director of Lyric Opera Theatre program

February 27, 2015

The announcement of William Reber’s retirement from his position as director in May 2015 signifies the end of an era for the ASU School of Music’s Lyric Opera Theatre (LOT). Since 1992, Reber has overseen more than 100 music theatre and opera performances.

Reber’s favorite thing about working on operas and musical theatre productions is the variety, for both himself and his students. “Many years I’d do the two operas and one or both main-stage musicals out of the four or five productions LOT produced. That provided a needed variation in style and rehearsal procedures, as well as allowing me to do works from both genres and using that as a teaching guide for our student conductors, pianists, and singers,” says Reber. Photo courtesy of Herberger Institute for Design and the Arts Download Full Image

The LOT is a community with a history of dedicated people who have worked with the program for long periods of time. As a testament to this longevity, there have only been two artistic directors since the program’s inception 24 years ago: Kenneth Seipp and Reber.

“I’ve had the opportunity to work with two outstanding and very different stage directors: Professor Dale Dreyfoos and Graham Whitehead, “says Reber. “Each has had unique insights into the productions we’ve done together, making each experience with them treasured memories.”

Dale Dreyfoos, interim director of the LOT, says, “Dr. Reber’s love of teaching is absolutely legendary, and we are all so much the richer for having had the wisdom and benefit of his example of what it takes to be a truly great teacher and mentor. No one can ever replace Dr. Reber as the ‘heart, mind and soul’ of Lyric Opera Theatre.”

Reber’s dedication has made the program grow in both size and excellence during his time as director. He believes his greatest accomplishments at ASU include developing the conducting programs in musical theatre and opera, which are two of only a few in the U.S. to address the specific knowledge required to be a successful music director for musical theatre or conductor in the opera pit.

As a combined program, LOT is unusual in that it produces both musicals and operas, allowing students to work in both areas and discover their true interest and talent.

“I’m also very appreciative of the support our program has consistently received not just from the School of Music but also from the Herberger Institute,” Reber says. “We have so many alums who are now working in one aspect of the profession or another. That is what makes me most proud about what has been accomplished here during the past 24 years.”

Reber’s leadership and focus on creating a positive experience for all students has made an indelible mark on the lives of the people with whom he has worked.

“I have enjoyed my time with Dr. Reber because he takes a vested interest in creating amazing music and helping students realize their potential,” says Jennifer Jones, Doctor of Musical Arts student in vocal performance. “Dr. Reber’s mentorship has provided me with a platform to explore this amazing field, and the impetus to perform at a professional level.”

“My favorite memory of Dr. Reber was on my cast’s last performance of ‘Cosi Fan Tutte,’ when we had a huge storm that flooded the basement of the [Music Building] where the orchestra pit is,” says Asleif Willmer, Doctor of Musical Arts student in vocal performance. “We almost had to cancel our performance, but Dr. Reber rose to the occasion and did the whole show himself on the piano. He had not played the opera in many years, but he is an amazing pianist and was the best orchestra we could ask for as singers.”

“Dr. Reber is a supportive mentor with a seemingly endless supply of useful information,” says Josef Curtis, Doctor of Musical Arts student in vocal performance. “I will always be indebted to him for the countless things I have learned both in coachings and in front of his baton.”

The ASU School of Music is holding a celebration in honor of Reber, beginning with the LOT performance of Benjamin Britten’s opera “Owen Wingrave,” at 2 p.m. on March 1, followed by a reception on the School of Music 3rd floor patio. The next day, on March 2, the festivities will continue with a gala concert featuring performances by faculty, current and former students from the LOT and vocal programs, at 7:30 p.m. at the Evelyn Smith Music Theatre.

“Benjamin Britten was still composing when I began my conducting training,” says Reber. “During my DMA studies, I enrolled in one of the first classes devoted to studying his operas. So, it was only natural that I identified with him and have found many occasions to perform his operas and non-theatrical works. This production will be my tenth Britten opera, the sixth at ASU.” 
Founded in 1964, LOT celebrated its 50th anniversary season during the 2013–2014 academic year. LOT presents five shows per season: two operas and two musicals and one student musical production. A search is currently underway to select Reber’s replacement.

From offbeat productions of little-known works to classic repertoire, the LOT program has prided itself on the variety of shows it produces. The 2014–2015 lineup of shows has included an opera double bill with “Dido and Aeneas” and “La Serva Padrona,” as well as “Owen Wingrave,” and the musicals “Children of Eden” and “Anything Goes.” This year’s student-produced workshop was “Reefer Madness.”

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Public Contact: 
Heather Beaman
Communications Liaison for the School of Music

Media Contact:
Heather Beaman
Communications Liaison for the School of Music