WORCESTER, Mass. — As the HIV/AIDS epidemic continues around the globe laying claim to more than 25 million lives and infecting over 39 million, researchers continue to search for both a cure and improved treatments for those suffering with this disease. Now the leading cause of death worldwide among 15 to 59 year olds, AIDS is a remarkably resilient adversary with the potent ability to evolve rapidly. This evolution dramatically complicates treatment, decreasing the effectiveness of existing drugs and necessitating the continual development of new therapeutics. University of Massachusetts Medical School Professor of Biochemistry & Molecular Pharmacology Celia A. Schiffer, PhD, is at the forefront of investigations to elucidate how HIV develops resistance to current drugs.
As a principal investigator of a National Institutes of Health Institute of General Medical Sciences Program Project Grant first awarded in 2001, Dr. Schiffer has comprised a stellar team of scientists from around the nation to develop HIV drugs that are less vulnerable to drug resistance. In recognition of the success of her efforts, Schiffer was recently awarded a full, five-year renewal of the project, “Targeting Ensembles of Drug Resistant HIV-Protease.” The renewal, totaling more than $8.5 million, will speed studies that seek a better understanding of inhibitor recognition and the development of new methodologies for designing inhibitors against HIV and other viruses and infections that have a propensity for acquiring drug resistance.
According to Terry R. Flotte, MD, executive deputy chancellor of UMMS and dean of the School of Medicine, the renewal reflects the NIH’s confidence in Schiffer’s scientific aims. “This work clearly illustrates how the advance of molecular biology can lead to direct benefit to patients. Dr. Schiffer's efforts to define exactly how HIV can become resistant to current drugs are vital to the development of better strategies to control HIV/AIDS.”
While highly active antiretroviral treatment (HAART) including inhibitors that target HIV-1 protease—a protein that allows viral maturation through cutting and releasing key viral components in the immature virus—has been remarkably successful in decreasing mortality, the emergence of mutations of HIV-1 that are resistant to current drug regimens is a critical factor in the clinical failure of antiviral therapy. With this renewed funding, Schiffer and colleagues will continue to address this challenge with a comprehensive approach that integrates clinical data, structural biology and biophysical chemistry, medical informatics and biostatistics, biochemistry and molecular virology, computational chemistry and computer-aided design, and synthetic and medicinal chemistry. The integrated program embraces two overarching goals: to clarify the role of compensatory mutations in HIV-1 protease in conferring drug resistance and to develop new HIV-1 protease inhibitors that are more robust against drug resistance.
“The occurrence of drug resistance negatively impacts the lives of millions of patients by limiting the longevity of many of our most promising new drugs. Through this integrated approach, we look forward to contributing to the development of drugs that promise to be more effective against HIV. Importantly, the new strategies we develop may also reduce drug resistance in other quickly evolving diseases, including lung cancer and hepatitis C,” Schiffer said.
To date, Schiffer and collaborators have made a number of advances. In 2004, for example, they were able to determine the crystal structures of many of the substrates—the sites HIV-1 protease cuts in the immature virus allowing viral maturation—and to compare their shape with the existing drugs. They found that while the sequences of the sites that are cuts were different, they all fit within a similar space, which they dubbed the “substrate envelope.” Significantly, the investigators found that most of the currently used inhibitors protrude beyond the substrate envelope, and many mutations that cause drug resistance occur where the inhibitors protrude away from the substrates. Drug resistance occurs since mutations at these positions limit drug binding, but allow HIV-1 protease to continue to function by recognizing and cutting substrates, thereby permitting the virus to mature.
In 2006, expanding upon this work the investigators reported on a new strategy to reduce the probability of drug resistance, by designing and synthesizing novel inhibitors to fit within the substrate envelope. This strategy should greatly retard the occurrence of drug resistance as any mutation that would confer drug resistance would simultaneously impact substrate recognition, thereby preventing HIV protease from functioning. Thus inhibitors developed by this method should be more robust against resistance occurring. Confirming the validity of this strategy, the scientists have designed, synthesized and are evaluating a novel series of highly potent HIV protease inhibitors that appear promising against drug resistant variants of HIV protease.
In addition to Schiffer, the principal investigator for the grant, other researchers closely involved include: UMMS Professor of Biochemistry and Molecular Pharmacology and Director of Chemical Biology Tariq Rana, PhD; Stanford University Medical Center Associate Professor Robert Shafer, MD; University of North Carolina School of Medicine Professor Ronald Swanstrom, PhD; and Massachusetts Institute of Technology Professor Bruce Tidor, PhD. Dr. Rana, in addition to his work on therapeutic RNAis, uses synthetic organic chemistry and high throughput chemical screens to focuses on HIV-related targets. Dr. Shafer is a physician specializing in drug resistance in infectious diseases and is the developer of a widely used patient-derived HIV sequence database of protease and reverse transcriptase. Dr. Swanstrom uses molecular virology and biochemistry on retroviruses in general and mechanisms of HIV drug-resistance in particular. Dr. Tidor develops computational methods for drug design utilizing the inverse design of optimal charge interactions and complementarity within a ligand binding pocket.
About the University of Massachusetts Medical School
The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $176 million in research funding annually, 80 percent of which comes from federal funding sources. The work of UMMS researcher Craig Mello, PhD, an investigator of the prestigious Howard Hughes Medical Institute (HHMI), and his colleague Andrew Fire, PhD, then of the Carnegie Institution of Washington, toward the discovery of RNA interference was awarded the 2006 Nobel Prize in Physiology or Medicine, hailed as the "Breakthrough of the Year" in 2002 by Science magazine and has spawned a new and promising field of research, the global impact of which may prove astounding. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information, visit www.umassmed.edu