USF researchers get grants to develop new drugs against flu bug
TAMPA, Fla. (Oct. 25, 2006) – Members of the University of South Florida’s drug discoverygroup, the Center for Molecular Diversity in Drug Design, Discovery, and Delivery, or CMD5,and collaborators, have received two USF, peer-reviewed grants to develop anti-viral drugs tofight influenza, a world-wide killer. The team will employ a new method - Target GuidedSynthesis (TGS) - to discover new compounds that could save time and money in the search fornew drugs to enlist in the battle against the flu bug.
Roman Manetsch and Edwin Rivera-Otero of the Department of Chemistry in the College ofArts and Sciences, and Alberto van Olphen in the Department of Global Health in the College ofPublic Health, received grants totaling $70,000 to develop drugs against influenza virus targets.
The grants, said the team, have helped consolidate their interdisciplinary research expertise in three fields - organic chemistry, molecular biology and biological nuclear magnetic resonance.
How could TGS aid in the discovery process and why is the process an improvement overtraditional methods for seeking new compounds? According to Manetsch, collections of compounds that normally react slowly to each other are,using TGS, exposed to a target enzyme. The enzyme acts to connect - into one molecule - thetwo reactive compounds that are found to bind best to each other. The traditional alternative -screening huge libraries of potentially useful compounds one at a time - is much more timeconsuming than TGS.
“The outcome of TGS is the selective formation of a single compound with improved biologicalactivity,” said Manetsch. "By targeting certain enzymes or proteins, TGS allows us to quicklyand inexpensively assay and identify potent compounds called ‘inhibitors,’ which act against thevirus.” In the effort to find new drugs to fight influenza A, for example, the effectiveness of this selection process depends on finding compounds to target Non-Structural Protein 1 (NS1), adominant protein in the influenza A virus.
“The influenza NS1 target serves to support joining two compounds and accelerates what wastheir unlikely fusion and fusion leads to a new molecule that binds more tightly to NS1 andinhibits the normal function of the protein,” said van Olphen, a microbiologist in the USF Centerfor Biological Defense. He contributes expertise in molecular biology and virology todevelopment of diagnostics and bioassays and protein expression and purification.
Alternately, the team could focus on the development of new anti-viral compounds to targetneuraminidase, another important viral enzyme. Developing a new neuraminidase inhibitorcould replace or complement the drug sold as “Tamiflu.” With health care professionals aroundthe world concerned about H5N1 infection, or “bird flu,” something is needed soon to replace or complement “Tamiflu,” which is expensive and in limited supply, explained Manetsch. Also,some strains of influenza have become resistant to it.
Today’s alternatives to “Tamiflu” include amantidine and rimantadine, a class of drugs currentlyused to target the M2 protein of influenza. Although used to treat commonly circulating strainsof flu, these drugs are generally not well-tolerated and are ineffective against avian flu.
Although the TGS process will greatly aid in the search for new drugs, even after likelycandidates are identified, challenges on the road to discovery must be overcome.
“After an inhibitor has been identified, three major questions remain,” said Rivera-Otero,director of the USF Interdisciplinary Nuclear Magnetic Resonance Facility. “We will need todetermine where the molecule binds to its target, precisely how does the molecule bind and howtightly the inhibitory molecule binds to the target” Using a technique known as nuclear magnetic resonance, or NMR, to analyze the molecules inquestion, the interdisciplinary team will address those important questions by monitoringmolecular changes at the atomic level. Rivera-Otero explains, magnetic field strengths limit thesize and resolution of the molecular complex that can be studied. The higher the magnetic fieldstrength, the larger the size of the complex that can be studied. Under certain conditions, NMRcan be useful in obtaining quick and preliminary data that will help to determine the mode ofbinding of the inhibitor and potentially to reduce the time for the drug discovery process.
“A more detailed study by NMR can also reveal the complete structure of the target with itsinhibitor in a liquid environment that mimics the cellular environment,” he said.
Not only will their work have the potential to lead to discovery, the unique nature of theircollaboration could impel other researchers toward new ideas.
“The interdisciplinary nature of our work can serve as a model or pattern to build researchcenters that support these and similar research initiatives,”said van Olphen, a veterinarian. Hisexperience includes the use of animal models for the study of viral pathogenesis and the efficacyof vaccines and therapeutics used against infectious agents.
The team plans to expand their influenza work to include other pathogens, especially those thatcould be used as bio-terror agents.
The University of South Florida is one of the nation’s top 63 public research universities as designated by the Carnegie Foundation for the Advancement of Teaching. USF received more than $310 million in research contracts and grants last year, and it is ranked by the National Science Foundation as one of the nation’s two fastest growing universities in terms of federal research and development expenditures. The university has a $1.6 billion annual budget and serves 44,038 students on campuses in Tampa, St. Petersburg, Sarasota/Manatee and Lakeland. USF is a member of the Big East Athletic Conference.


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