"I and the scientists I work with believe antiretrovirals are probably the most rational approach for preventing HIV infection," she says. "We think they are going to be the key for stemming the epidemic of HIV." Kashuba is an associate professor at the UNC Eshelman School of Pharmacy and director of the Clinical Pharmacology and Analytical Chemistry Core of the UNC Center for AIDS Research.

The National Institute of Allergies and Infectious Diseases has awarded her a $100,000 planning grant for her proposal, "Preventing HIV Infection in Women: Targeting Antiretrovirals to Mucosal Tissues." The planning grant is the first step in a process that Kashuba hopes will result in clinical trials to develop a pharmacokinetic-pharmacodynamic model that can predict the right dosage of antiretroviral drugs needed to achieve the optimum concentration of those drugs in the body to prevent infection by HIV.

"I am focused on providing some rational clinical pharmacology to the HIV-prevention community to choose the right drugs, the right doses, the right combination of drugs, the right regimen to put into a clinical trial for HIV prevention," Kashuba says. "The fact that NIAID has awarded this grant means that they believe in this approach and are very interested in working with us."

Kashuba says she is planning a series of clinical studies in HIV-negative women to evaluate the drug exposure in mucosal surfaces that are susceptible to HIV infections (vaginal, rectal, and cervical tissue). Using these data along with data generated from a novel tissue-culture system that can be infected with various strains of HIV, she would then develop a pharmacokinetic-pharmacodynamic model that will give researchers the proper dosage needed to achieve the desired concentration of drugs in the tissue. In other words, the model would tell scientists how much medicine a person needed to take to protect themselves from HIV.

"Although we know the effective concentrations we need to treat someone for HIV, we've never worked out what concentration of drugs we need to prevent HIV infection," Kashuba says. "We've developed a rather novel model where we can infect human tissue with HIV, put drugs on the tissue, and define for the first time the right concentration protect that tissue against HIV."

There are currently seven infection-prevention clinical trials going on around the world using one or two antiretroviral drugs, drugs that have been tested in animals but at much higher doses than the ones the approximately 10,000 participants are receiving, she says.

"We have no preliminary data about whether these drugs at the doses given are actually going to work. While I am hopeful that at least one of these approaches will have some effect,  the results probably will not be optimal."

Kashuba's work is focused on protecting uninfected people, particularly women in the developing world who for social, cultural, or religious reasons cannot take steps to protect themselves that would be apparent to a partner. Kashuba is collaborating on the project with Myron Cohen, MD, the J. Herbert Bate Distinguished Professor of Medicine and Microbiology, Immunology, and Public Health and director of the UNC Center for Infectious Diseases; clinical assistant professor Kristine Patterson, MD, and assistant professor Gretchen Stuart, MD, MPH, all from the UNC School of Medicine, as well as Nicholas Shaheen, MD, MPH, associate professor of medicine and epidemiology in the UNC Gillings School of Global Public Health.

Peter Koval, PharmD

Peter Gal, PharmD

Peter Gal, PharmD, and Pete Koval, PharmD, faculty members in the Division of Pharmacy Practice and Experiential Education, have received Lenovo Innovation Grants from the UNC Center for Faculty Excellence to develop projects in Second Life to help students in real life.

Gal, a clinical professor, will use his $9,900 grant to create an orientation program on the virtual-reality social network to familiarize fourth-year doctor of pharmacy students with clinical practice in a neonatal intensive care unit (NICU) before they begin that portion of their practice-experience curriculum. Gal oversees the neonatal pharmacotherapy fellowship at the NICU at The Women’s Hospital of Greensboro, which trains twelve to fifteen fourth-year PharmD students from the UNC Eshelman School of Pharmacy each year.

“Most pharmacy students in the United States or around the world have never experienced, virtually or in real life, the complicated clinical practice of the neonatal intensive care unit,” says Gal, director of graduate pharmacy education at the Greensboro Area Health Education Center. “Providing a virtual experience may be useful for orienting students to a workplace and improving the student’s ability to perform required pharmacist tasks in the real-world setting.”

Gal’s team will develop interactive neonatal device models and practical patient-monitoring exercises that will allow students to identify and practice the skills a pharmacist will need in an NICU. Students will be assessed through interactive technology, including a quiz. The model will first be used in a pilot program for UNC students and then shared with other pharmacy schools.

Koval, a clinical associate professor and assistant director of pharmacotherapy, education, and research at the Greensboro AHEC, received a $9,030 grant to study the value of using a virtual poster demonstration to prepare students for a live presentation.

Koval’s project will develop poster-presentation venues in Second Life for the fourth-year PharmD students at the School who participate in the Clinical Scholars Program. As part of the program, they must present a completed research project at a professional meeting, a requirement most commonly fulfilled with a poster presentation at the spring meeting of the North Carolina Association of Pharmacists.

“This is the first professional presentation of research for most of these students,” Koval says. “The goal of this project is to enhance students’ skill, ability, and confidence to present research findings visually and verbally.”

In Koval’s project, half of the approximately forty students who participate in the Clinical Scholars Program each year will give a virtual presentation in Second Life before their live presentations. Pharmacy faculty from around the state, many of whom would not be able to attend live presentations in person, will be invited to interact with students in the virtual environment and give them verbal feedback and standardized written evaluations. Faculty and students will be surveyed after the virtual and live presentations for their assessment of how much the Second Life experience helped the students prepare. These students’ performance in the live presentation will also be compared with that of the Clinical Scholars Program participants who did not give a virtual presentation.

“This project addresses one of our core curricular goals—to improve communication skills, including the ability to clearly explain clinical information,” says Koval, who is also a collaborator on Gal’s project.

SHAC is composed of students from all UNC health-affairs schools: pharmacy, medicine, nursing, dentistry, public health, and social work. The students provide free health services to local underserved individuals and communities, partner with communities to develop and implement sustainable programs, and create service-learning environments for students in the health-science programs at UNC. The students from the UNC Eshelman School of Pharmacy whom the award recognizes are team leader Carson P. Padgett (PY3), Kathryn G. Merkel (PY4), LaKia S. Scoggins (PY4), Allison L. Snyder (PY3), and Christopher J. Westerfield (PY3). Lisa M. Dinkins, PharmD, a clinical assistant professor in the Division of Pharmacy Practice and Experiential Education, is their faculty adviser.

The key branches of SHAC in which pharmacy students are currently involved include the SHAC Clinic in Carrboro, SHAC Outreach and Beyond Clinic Walls. all of which allow student practitioners to work in teams to solve complex medical and lifestyle concerns for their patients.

• At the clinic, pharmacy students consult with medical teams of one or two medical students with an attending physician and make recommendations for medication therapy. They encourage adherence to the SHAC formulary when possible, which guarantees that the patient will receive the medications they need free of charge.
• SHAC Outreach works with local groups to assess ways for community members to get involved in maintaining and improving their health. Students identify unmet needs, partner with groups to create sustainable programs and provide support through materials, expertise and volunteers. Examples of outreach initiatives include diabetes clinics, health fairs, and wellness programs.
• In Beyond Clinic Walls, students form interdisciplinary teams and visit a client's home monthly to assess the client's health status, living conditions, and concerns, and then share their observations with the client's primary-care physician. Pharmacy students are responsible for documenting and updating a list of medications for each client, monitoring their client for medication contraindications and adverse side effects, and reporting any concerns to their team leader. Students also assess their client's compliance and knowledge about their medications and provide education as needed.

The UNC students

In addition to receiving a commemorative Steuben glass Star Stream, the winning schools will also receive $10,000 to be used exclusively to support the expansion of the recognized program or new community engaged service projects at the school. Additional prizes include a $5,000 financial stipend administered to participating students to be used for enhancing or sustaining the recognized program or for travel support to attend and present their projects at professional meetings.

A student representative and faculty adviser from each winning school  will be honored during the 2010 AACP Interim Meeting Community Engaged Service Awards Luncheon on Monday, February 8, at the Crystal Gateway Marriott Hotel in Arlington, Virginia.
 

	Fred Eshelman

Chancellor Holden Thorp and the trustees honored Fred Eshelman, founder of PPD Inc., of Wilmington; Richard Krasno, executive director of the William R. Kenan Jr. Charitable Trust, of Chapel Hill; Gov. Beverly Perdue of Raleigh; and Richard “Stick” Williams, senior vice president of environmental health and safety at Duke Energy Corp., of Charlotte during a dinner Wednesday, November 18, at the Carolina Inn.

Established by the Board of Trustees in 1984, the Davie Award is named for the Revolutionary War hero who is considered the father of the University. It recognizes extraordinary service to the University or society.

With his vision and generosity, Eshelman dramatically enhanced the University's pharmacy school, now named the Eshelman School of Pharmacy in his honor. The 1972 graduate of the school has supported Carolina with his commitment of time, service, and gifts totaling more than $33 million.

Eshelman has been a member of the pharmacy school’s Board of Visitors for more than a decade and has lectured as an adjunct faculty member. With each of his gifts, he has strategically improved the school. He created five $1 million distinguished professorships that helped to recruit world-renowned faculty. He established six scholarships for doctor of pharmacy students in addition to fellowships that last year were awarded to eight graduate students. He provided seed money to begin construction of the school’s 70,000 square feet of laboratory space in the new Genetic Medicine Building. He established a Fund for Excellence to support innovation at the school.

Because of Eshelman’s support, the school has added expert faculty in many disciplines, enrolled promising students from around the country and world and increased faculty research funding from the National Institutes of Health.

This is the second consecutive year that a School alum has received the Davie Award. Vaughn and Nancy Bryson, both 1960 graduates of the School, received the honor in 2008.

Photos of the hands-on sessions

“We are moving into the frontier of personalized medicine and are treating patients not just by the site of their tumor but by the genetic composition of their disease and of their normal DNA,” Schilsky told the U.S. House of Representatives in March, “This enables us to determine which patients will benefit from a treatment, and just as importantly, which patients will not benefit from a treatment.”

The IPIT Award for Clinical Service annually honors a person who has made significant direct contributions to the advancement of individualized therapy in clinical practice. The award acknowledges Schilsky’s long-standing efforts to further the notion and practice of individualizing care for cancer.

“Dr. Schilsky has been directly responsible for shifting the discussion from ‘should we’ to ‘how do we’ pursue individualized cancer therapy,” says Howard McLeod, director of IPIT and Fred Eshelman Professor of Pharmacy at the UNC Eshelman School of Pharmacy.

Schilsky is president of the American Society of Clinical Oncologists and section chief of hematology/oncology at the University of Chicago Medical Center. He will receive the award and present a seminar entitled “Personalized Cancer Care: Research, Policy, and Practice” on November 19, at 3:00 p.m. in the Joseph Pagano Conference Room in the Lineberger Comprehensive Cancer Center on the UNC-Chapel Hill campus.

“As ASCO president last year, Dr Schilsky chose the emerging science of personalized cancer care based on pharmacogenetics as his flagship issue,” says Richard Goldberg, MD, chief of the Division of Hematology/Oncology at the UNC School of Medicine and physician-in-chief of the new North Carolina Cancer Hospital. “His advocacy for practicing medicine based on individual patients rather than a generic approach has helped to move the field forward.”

Since 1995 Schilsky has served as chair of Cancer and Leukemia Group B, a cooperative group sponsored by the National Cancer Institute that conducts clinical trials in cancer treatment, biology, prevention, and health outcomes. His laboratory and clinical research have been continuously funded by the NCI since 1987. As the current president of ASCO, he champions the clinical-trials model to ensure that high quality, evidence-based practices for the prevention, diagnosis, and treatment of cancer are available to each individual American citizen.

Richard M. Schilsky, MD

Schilsky earned his MD at the University of Chicago Pritzker School of Medicine in 1975. Following a residency in Internal Medicine at the University of Texas Southwestern Medical Center and Parkland Memorial Hospital, he received training in medical oncology and clinical pharmacology at the National Cancer Institute from 1977 to 1981. He then served as assistant professor of medicine at the University of Missouri-Columbia School of Medicine from 1981 to 1984 when he returned to the University of Chicago where he is presently professor of medicine (tenured). Schilsky previously served as director of the University of Chicago Cancer Research Center from 1991 to 1999 and as associate dean for clinical research from 1999 to 2007.

As an international expert in gastrointestinal malignancies and cancer pharmacology, he has served on a number of peer-review and advisory committees for the NCI and previously served as chair of the Oncologic Drugs Advisory Committee for the FDA.. Schilsky currently serves as chair of the NCI Board of Scientific Advisors and as a member of the Clinical and Translational Research Advisory Committee. Schilsky has served as a member of the board of directors of the American Society of Clinical Oncology.

UNC Institute for Pharmacogenomics and Individualized Therapy

The institute was formed in the UNC Eshelman School of Pharmacy as a collaborative effort with the School of Medicine, Gillings School of Global Public Health, and the School of Nursing and with support from the UNC Lineberger Comprehensive Cancer Center and the Carolina Center for Genome Sciences. Pharmacogenomics is the study of how genetic variation among individuals contributes to differences in the way people respond to medicines.

Leadership in key areas of pharmacogenomic research is fostered by contiguous office and laboratory space that bolster collaboration and enable the development of comprehensive research investigations and treatment tools. IPIT also offers the services of core facilities in molecular genomics, cellular phenotyping and bioinformatics to add to the excellent core facilities already existing at UNC.

For more information, please visit: www.ipit.unc.edu.

The honor recognizes individuals who have made sustained, remarkable scholarly and research contributions to the pharmaceutical sciences, such as original articles, scientific presentations at AAPS Annual Meetings, and patents.

Mumper is the John A. McNeill Distinguished Professor in the Division of Molecular Pharmaceutics and director of the School’s Center for Nanotechnology in Drug Delivery. His research on the creation of drug-, gene-, and vaccine-delivery systems has led to several first-in-human studies in the past twenty years. His current research focuses on nanoparticle-based systems to overcome resistance in cancer and their use as vaccine-delivery systems to co-deliver protein antigens and adjuvants. Over the past ten years, Mumper has led seven university-based product development efforts resulting in first-in-human clinical trials.

McLeod's specialty is pharmacogenomics, the science of matching medicines to the unique genetic makeup of a patient, or as McLeod say, "getting the right drug to the right person at the right time." The ad focuses on his work with breast cancer patients and the drug tamoxifen, which kills cancer cells. Oncologists were calling McLeod and asking him why the regular dose of tamoxifen wasn’t having a positive effect on their patients. In studying the women’s genes, McLeod and his team discovered that approximately half of breast cancer patients do not respond to the typical dose. This group needs a dose specialized just for them. McLeod's work led to the FDA changing dosing recommendations for the drug.

You can read more stories like this at one.unc.edu.  You can view the TV spot featuring McLeod by clicking on the video below.

The researchers developed a computational method that compares how similar the structures of all known drugs are to the naturally occurring binding partners -- known as ligands -- of disease targets within the cell. In a study published this week in Nature, the scientists showed that the method predicts potential new uses as well as unexpected side effects of approved drugs.

Bryan Roth, MD, PhD

“This approach uncovered interactions between drugs and targets that we never could have predicted simply by looking at the chemical structures,” said senior study author Bryan Roth, MD, PhD, a professor in the Division of Medicinal Chemistry and Natural Products and director of the National Institute of Mental Health Psychoactive Drug Screening Program at UNC. “We may now have a way to predict what side effects are likely to occur from treatment before we even put a drug into clinical testing.” 

Roth is also a professor of pharmacology in the UNC School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center.

Many of the most successful drugs on the market today are being prescribed for ailments that are quite different from the ones they were originally designed to treat. Viagra, for instance, was once intended for coronary heart disease but now is used to combat erectile dysfunction. The discovery of surprising uses of developed drugs can sometimes be the result of serendipity, as unforeseen side effects emerge from clinical trials. In the past, researchers have tried to predict drug interactions by looking for chemical similarities among the possible targets of pharmaceutical compounds.

However, some drug targets which look very similar to one another bind very different ligands, and some targets that don't have any obvious similarity bind similar ligands, says Brian Shoichet, PhD., co-senior study author and professor of pharmaceutical chemistry at UCSF. “So if instead we were to organize targets by the ligands they recognize, it could reveal different patterns than traditional approaches, and illuminate new opportunities for drugs to bind to unexpected targets.”

A team of researchers led by Roth and Shoichet did just that, comparing the structures of 3,365 FDA-approved and investigational drugs against the structures of hundreds of targets, defining each target by its ligands. They then honed in on thirty of the strongest predictions, validating the actual physical interactions between the drugs and targets in wet laboratory experiments.

In one of their follow-up experiments, the scientists investigated the molecular targets of the hallucinogenic substance dimethyltrytamine (DMT), which had previously been postulated to act through a site known as the sigma-1 receptor. Using the computational approach, Roth and colleagues found that DMT had a high affinity for serotonin receptors, including the binding site for LSD, another hallucinogen.

They also showed that the substance is hallucinogenic in normal mouse models but not in ones lacking the serotonin receptor. Roth says the power of their approach is it can be used to uncover the real targets of pharmaceutical compounds quickly and efficiently, and will probably lead to a greater understanding of the many molecular targets of each drug.

“Drugs are not as selective as we once thought,” said Roth, who is also a professor in the School of Pharmacy’s medicinal chemistry and natural products division. “It turns out that the most non-selective drugs are frequently the most effective for complex diseases. Rather than ‘magic bullets,’ we need to come up with ‘magic shotguns’ that hit more than one molecular target at a time. We could use this computational approach to identify the drugs that hit the right targets and miss the wrong ones.”

Study co-authors from UNC include Vincent Setola, research associate professor; Atheir Abbas, former graduate student; Sandra J. Hufeisen, senior research assistant; Niels H. Jensen, research associate; Michael B. Kuijer, research technician; Roberto C. Matos, research technician; Thuy B. Tran, research technician; Ryan Whaley, research technician; and Richard A. Glennon.  The paper’s first author is Dr. Michael Keiser, from the UCSF side of the collaboration.  Also from UCSF were Drs. John Irwin, Christian Laggner and Jerome Hert, and PharmDs Kelan Thomas and Douglas Edwards.

Funding for the studies at UNC and at UCSF came from the National Institutes of Health.

Kim Thrasher, PharmD

Peter Koval,
PharmD

Two clinical associate professors at the UNC Eshelman School of Pharmacy will serve on a new Board of Pharmaceutical Specialties council to develop a certification for ambulatory-care pharmacy specialists.

Peter Koval, PharmD, and Kim Thrasher, PharmD, are both board certified pharmacotherapy specialists and faculty members in the School's Division of Pharmacy Practice and Experiential Education. Koval is also the associate director of pharmacotherapy at the Greensboro Area Health Education Center, while Thrasher serves the same role at the South East AHEC.

The BPS is an independent certification agency of the American Pharmacists Association that recognizes specialties and certifies pharmacists in areas of specialty pharmacy practice. In June 2009, the BPS approved a joint petition from the APhA, the American College of Clinical Pharmacy, and the American Society of Health-System Pharmacists to recognize ambulatory care pharmacy practice as the sixth specialty in which pharmacists can be board-certified.

Each of the three organizations that submitted the petition will have three appointees on the new specialty council, whose responsibilities will include developing an ambulatory care specialty certification examination. Koval and Thrasher will represent the ACCP on the specialty council.

The other five BPS-certified specialties are: nuclear pharmacy, nutrition support pharmacy, oncology pharmacy, pharmacotherapy, and psychiatric pharmacy.

This annual award from the institute honors a person who has made significant contribution to the advancement of rational drug-therapy initiatives across society. The award acknowledges McClellan’s advocacy of pharmacogenomics and personalized medicine throughout his career. Currently the director of the Engelberg Center for Health Care Reform at the Brookings Institution, he has also served as commissioner of the Food and Drug Administration and administrator of the Centers for Medicare & Medicaid Services. McClellan, who is both a medical doctor and economist, will receive the award and present a seminar on November 5 at 4:00 p.m. in the Blue Cross Blue Shield Auditorium of the UNC Gillings School of Global Public Health on the Chapel Hill campus (click for a map). A reception will immediately follow.

“Dr. McClellan has been willing to lead by example, making policy that puts the individual patient in a place of priority,” says Howard McLeod, PharmD, director of IPIT and the Fred Eshelman Distinguished Professor. “The fact that the FDA and CMMS take pharmacogenomics seriously has caused medical practice to follow suit.”

McClellan’s work at the Engelberg center focuses on developing practical policy solutions for health-care reform that will reduce the growth of health-care spending and improve quality. He also continues to be a driving force for personalizing the health care that Americans receive. Under his leadership, a range of center initiatives are focused on improving the development of and regulatory science for more personalized therapies in cancer and neuro-degenerative diseases, as well as effectively implementing comparative effectiveness research that advances individualized care. 

“If we do it right, health-care reform can have a positive impact on medical innovation and our overall ability to deliver the best, most targeted care to patients,” McClellan says. 

As FDA commissioner, McClellan oversaw efforts to establish a new regulatory approach for using pharmacogenomic information in product development and the creation of electronic data systems that would enhance the analysis of collected pharmacogenomics data. 

“We believe that better analysis of pharmacogenomics data can close the information gaps as to why people respond differently to the same drug,” he says. “These steps toward developing better, more comprehensive information on treatments at a lower cost are especially important to patients so that we can do a better job of telling patients exactly which treatments are best for them.”

Mark McClellan, MD, PhD

Mark McClellan is senior fellow, director of the Engelberg Center for Health Care Reform, and Leonard D. Schaeffer Chair in Health Policy Studies at the Brookings Institution. Established in 2007, the Engelberg Center provides practical solutions to achieve high-quality, innovative, affordable health care with particular emphasis on identifying opportunities on the national, state, and local levels.

A doctor and economist by training, McClellan has a highly distinguished record in public service and academic research. He is a former administrator of the Centers for Medicare & Medicaid Services and former commissioner of the Food and Drug Administration. McClellan served as a member of the President’s Council of Economic Advisers and senior director for health-care policy under President George W. Bush. He also served in the Clinton administration as deputy assistant secretary of the Treasury for economic policy where he supervised economic analysis and policy development on a range of domestic policy issues.

Previously, McClellan was an associate professor of economics and associate professor of medicine with tenure at Stanford University where he directed Stanford’s Program on Health Outcomes Research; served as associate editor of the Journal of Health Economics, and was coprincipal investigator of the Health and Retirement Study, a longitudinal study of the health and economic status of older Americans.  He has twice received the Kenneth J. Arrow Award for Outstanding Research in Health Economics.

In his capacity as a health-policy expert, McClellan is the codirector of the Bipartisan Policy Center’s Leaders’ Project on the State of American Health Care; cochair of the Robert Wood Johnson Foundation Commission to Build a Healthier America; and chair of the FDA’s Reagan-Udall Foundation. He is also cochair of the Quality Alliance Steering Committee, sits on the National Quality Forum’s Board of Directors, is a member of the Institute of Medicine of the National Academy of Sciences, and is a research associate at the National Bureau of Economic Research. 

McClellan holds an MD from the Harvard University–Massachusetts Institute of Technology ] Division of Health Sciences and Technology, a PhD in economics from MIT, an MPA from Harvard University, and a BA from the University of Texas at Austin.  He completed his residency training in internal medicine at Brigham and Women's Hospital in Boston, is board certified in internal medicine, and has been a practicing internist during his career.

UNC Institute for Pharmacogenomics and Individualized Therapy

The institute was formed in the UNC Eshelman School of Pharmacy as a collaborative effort with the School of Medicine, Gillings School of Global Public Health, and the School of Nursing and with support from the UNC Lineberger Comprehensive Cancer Center and the Carolina Center for Genome Sciences. Pharmacogenomics is the study of how genetic variation among individuals contributes to differences in the way people respond to medicines.

Leadership in key areas of pharmacogenomic research is fostered by contiguous office and laboratory space that bolster collaboration and enable the development of comprehensive research investigations and treatment tools. IPIT also offers the services of core facilities in molecular genomics, cellular phenotyping and bioinformatics to add to the excellent core facilities already existing at UNC.

DeSimone is the Chancellor’s Eminent Professor of Chemistry in the College of Arts and Sciences and holds a joint appointment in the School’s Division of Molecular Pharmaceutics. His research focuses on nanomedicine and drug delivery. He has developed techniques for mass-producing custom-made micro- and nanoparticles tailored to have specific sizes, shapes and surface properties. That technology, known as PRINT (Particle Replication in Non-wetting Templates), is exclusively licensed to a UNC spin-off company in Research Triangle Park. DeSimone recently received the Pioneer Award from the National Institutes of Health to support efforts to build on his research and develop new methods to safely and effectively deliver promising biological therapeutics to specific locations in the body.

DeSimone and five others will receive the North Carolina Award from Governor Bev Perdue and Linda A. Carlisle, the N.C. Department of Cultural Resources Secretary in a ceremony at the N.C. Museum of History.

“This is a fundamental change in the way we understand the simple act of binding, which is important not only for biology but for drug development.” says Lee, a professor in the School’s Division of Medicinal Chemistry and Natural Products. “This mechanism has never been seen before in single protein domains whose job it is to simply bind something. It is a nice, clear example of protein dynamics affecting protein function.”

Lee’s team studied the third PDZ domain of protein PSD-95, which is commonly found in neural synapses. PSD-95 is a scaffolding protein, attracting and joining other proteins so that those proteins can communicate with each other. The PDZ domain is the binding site where other proteins join with PSD-95.

“The fundamental function of PDZ domains is to serve as molecular Velcro,” Lee says. “PDZ domain structure and function is well understood at this point. In fact, this third PDZ domain on PSD95 is the archetypal PDZ domain. It was the first one that was solved structurally.”

A protein domain is a section of a protein that can exist separately from the rest of the protein. Many proteins consist of several domains. PDZ domains are found in signaling proteins of many different organisms and are named for the first three proteins that were discovered that shared the domain.

“What we found interesting about this particular PDZ domain is that it has a piece of structure that most PDZ domains don’t have,” Lee says of the third PDZ domain of PSD-95. “We wanted to know why, so we lopped it off and tested PSD-95 for function.”

Lee discovered that by removing the extra bit of structure, called an alpha helix, PSD-95’s affinity for binding to a certain peptide, or protein tail, of the protein CRIPT was reduced twenty-fold. The findings are published October 13, 2009, in  the Proceedings of the National Academy of Sciences in an article titled “Hidden Dynamic Allostery in a PDZ Domain.”

“While the helix is in the PDZ domain, it is not part of the actual binding site, so the question is how is it affecting the binding site if the structure isn’t changing at all?” Lee says.

Using nuclear magnetic resonance spectroscopy, the researchers examined the domain in four different states: with and without the alpha helix and with and without the CRIPT peptides. Removing the alpha helix caused the structure of the protein to become more rigid without changing configuration, Lee says.

“To move from a flexible to a rigid state, the protein must pay a cost in energy,” he says. “This mechanism has never been seen before in single protein domains whose job it is to simply bind something.”

Lee says that this finding is significant because this nonstructural mechanism for manipulating binding function by “removing” the alpha helix may actually be used in neurons since the alpha helix may accept a phosphate group. Phosphorylation could essentially remove the helix and reduce binding function. Also, the discovery raises the possibility that other types of protein domains may be affected by this type of mechanism, he says.

Lee is the senior author of the paper. The other authors are Chad M Petit, PhD, and Paul J Sapienza, PhD, postdoctoral fellows in the UNC Eshelman School of Pharmacy; Jun Zhang, a graduate student in the UNC School of Medicine; and Ernesto J. Fuentes, PhD, assistant professor of biochemistry at the University of Iowa. The work was funded by a grant from the National Science Foundation.

The grant will support Schuck’s dissertation research study of the enzyme 5-lipoxygenase (ALOX5). ALOX5 synthesizes fatty molecules called leukotrienes, which promote inflammation. Genetic variation in ALOX5 has been associated with the development of cardiovascular disease, but the reason remains unclear. Schuck’s study will try to determine whether cardiovascular disease patients with a genetic variant in their ALOX5 have higher levels of leukotrienes and inflammatory markers.

“Ultimately this project could help identify patients who would benefit from therapies that decrease the production of leukotrienes,” says Schuck, who joined the School’s graduate program in the Division of Pharmacotherapy and Experimental Therapeutics in 2008 after earning his doctor of pharmacy from the University of Michigan..

The grant, titled “Functional Characterization of a 5-Lipoxygenase Polymorphism in Patients with Atherosclerotic Cardiovascular Disease”, was one of four chosen for funding out of eleven applications. TraC$2K grants assist researchers in implementing a proposed study or move a research project forward by providing rapid access to funds that will support almost any aspect of promising and innovative research.

“We are grateful to the UNC TraCS Institute for their support of this pilot project,” says Craig Lee, PharmD, PhD, Schuck’s adviser. “Training the next generation of translational scientists is a core mission of both our graduate program in DPET and the UNC TraCS Institute.”

Stephen Frye, PhD, "Discovery of Small Molecule MBT Domain Antagonists"

Frye received a two-year $873,000 challenge grant to study proteins involved in chromatin regulation. He will develop molecular probes to explore the regulation of the cellular genetic material called chromatin and how chromatin's control of gene expression and gene silencing is relevant in normal and disease biology. When the proteins that control chromatin are deranged, cancer can develop.

Frye is director of the Center for Integrative Chemical Biology and Drug Discovery and a professor in the Division of Medicinal Chemistry and Natural Products. He is also a member of UNC Lineberger Comprehensive Cancer Center.

Andrew Lee, PhD, “Dynamic Networks and Mechanisms of Allosteric Communication in Proteins”

Lee received $97,556 to support his work studying the internal movement and communication of protein molecules. Proteins are the body’s molecular machines and are popular targets for drugs as blocking a protein’s function can slow or stop a biological process. Lee studies how proteins transmit information about what is happening at one site on their structure to more distant points along the molecule. This communication can affect structure, movement, and energy at other points on the protein, including potential drug binding sites.

Lee is an associate professor in the Division of Medicinal Chemistry and Natural Products.

Mary Paine, PhD, “Mechanisms Underlying Drug-Diet Interaction”

Paine has been awarded $342,592 to study whether milk thistle products should be avoided when taking certain medications. Milk thistle extracts, are taken by many people in hopes of preventing liver damage and as a treatment for liver diseases such as hepatitis and cirrhosis. Because milk thistle acts on the liver where many drugs are metabolized, there is the potential for it to interact or interfere with those drugs.

Paine an assistant professor in the Division of Pharmacotherapy and Experimental Therapeutics,

Alex Tropsha, PhD, “Predictive QSAR Modeling”

Tropsha has received $730,789 to support his work in developing a faster, more accurate drug-design technique based on cheminformatics, an approach that mixes the disciplines of chemistry and computer science. Here is his description of his project in his own words.

“There are two major computational approaches to drug design: ligand based and structure based. The former only uses the information on organic molecules tested in experimental assays that are considered relevant; i.e., molecules found active in such assays are expected to be clinical candidates against specific diseases (e.g., active inhibitors of HIV protease are potential drugs combating HIV). The parent grant of this new application is aimed at the development of novel computational approaches for ligand-based drug design based on the concepts of a research discipline known as cheminformatics.

The alternative approach is structure-based design, which utilizes the knowledge of experimentally determined (by x-ray or NMR) three-dimensional structure of protein or nucleic-acid targets (e.g., HIV protease). This information is used to discover organic molecules that are stereochemically complementary to the active sites of the target proteins.  The computational approaches used in this case, specifically docking (i.e., simulation of ligand binding to the receptor) and scoring, are part of a discipline known as structural bioinformatics.

My new proposal bridges these two approaches in a new way. Specifically, we employ cheminformatics concepts but apply them to characterize three-dimensional binding sites of protein structure. This approach is expected to be orders of magnitude faster than current structure-based methodologies yet rival them in accuracy.”

Tropsha is chair of the Division of Medicinal Chemistry and Natural Products and the K. H. Lee Distinguished Professor.

The University has set up a Web page with details on ARRA grants at Carolina. More information about NIH’s ARRA grant-funding opportunities can be found at http://grants.nih.gov/recovery/. To track the progress of HHS activities funded through the ARRA, visit www.hhs.gov/recovery.