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Emerging subtypes of influenza A virus clutch the potential to initiate a world remote epidemic in the next small in number years, according to World Health Organization officials. However, not quite all type A influenza viral strains have become resistant to amantadine and rimantadine, two drugs that make up one of only two classes used to treat the flu.

Researchers at the University of Pennsylvania School of Medicine have now provided a new strategy for insidious drugs that target the resistant viral strains by solving the three-dimensional arrangement of a viral protein called the M2 proton channel. This protein is the molecular receptor as being these drugs. This study is published in the Jan. 31 issue of the journal Nature.

The M2 protein is located in the viral wrapper, forming a long, narrow channel that allows the flow of protons into the viral interior, an essential step for infection. Amantadine sits in this duct and blocks the flow of protons, thus halting infection. In non-resistant viruses, amantadine acts like a cork lodged deep in the channel.

“We apprehend that resistance to amantadine is caused by a mutation in the poison M2 protein, but we did not know for what reason this mutation caused resistance,” explains senior author William F. DeGrado, PhD, Professor of Biochemistry and Biophysics. “Now we do the mutation changes the shape of the channel so amantadine can no longer do its job.”

The structure revealed that there is a pocket in the channel next to the location where amantadine fits that is conserved in all influenza A viruses. This newly discovered room could be the target for new drugs. “Inhibitors that target this cavity adjacent to two highly conserved amino acids in M2 might reclaim the M2-blocking class of drugs so that ongoing endemic outbreaks and future pandemics of this deadly virus might be prevented and treated,” says DeGrado.

“The crystal structures of influenza M2 with and without the anti-influenza drug help us understand the molecular basis of drug resistance, which is a serious problem in treating the flu,” said Jean Chin, PhD, who oversees grants on membrane proteins at the National Institute of General Medical Sciences, which in part funded this research. “The findings will inspire scientists working to design the next generation of antivirals.”

The M2 protein was crystallized so that its structure could be examined under different conditions. This allowed the Penn research team, which included Amanda Stouffer, Rudresh Acharya, David Salom, Cinque Soto, Luigi Di Costanzo, Steven Stayrook, Vikas Nanda, and Anna Levine, to determine the structure of the crystallized protein using a technique called x-ray crystallography.

The stainless protein crystal was bombarded with x-rays so that the position of each atom in relation to its neighboring atoms in the crystal would show up as an rich garments. of black spots. From the pattern of thousands of spots, the structure of the protein be able to be graphically visualized using computer imaging technology.

The next gait is to design new compounds that quid the M2 channel by fitting into the newly discovered larger cavity. The Penn examination group is currently engaged in these studies.

This study was supported by the National Institute of General Medical Studies, the Kimberly and Margaret DeLape Fellowship, the University of Pennsylvania’s MRSEC program, and the National Science Foundation.

Valentina Tereshko of the University of Chicago also contributed to this study.

PENN Medicine is a $3.5 billion endeavor dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System.

Penn’s School of Medicine is currently ranked #3 in the nation in U.S. News & World Report’s survey of top research-oriented medical schools; and, according to most recent facts from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the race’s “Honor Roll” hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation’s first hospital; and Penn Presbyterian Medical Center a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

University of Pennsylvania School of Medicine
3600 Market St., Ste 240
Philadelphia, PA 19104
United States
http://www.med.upenn.edu

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This entry was posted on Thursday, January 31st, 2008 at 8:02 am and is filed under Uncategorized. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.