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Posted: Jun 2nd, 2012 Computer-designed proteins programmed to disarm variety of fluviruses ( Nanowerk News ) Computer-designed proteins are under construction to fight theflu. Researchers are demonstrating that proteins found in nature,but that do not normally bind the flu, can be engineered to act asbroad-spectrum antiviral agents against a variety of flu virusstrains, including H1N1 pandemic influenza. "One of these engineered proteins has a flu-fighting potency thatrivals that of several human monoclonal antibodies," said Dr. DavidBaker, professor of biochemistry at the University of Washington,in a report in Nature Biotechnology ( "Optimization of affinity, specificity and function ofdesigned influenza inhibitors using deep sequencing" ). An H3N2 strain of influenza virus. The virus is about 120nanometers, or one ten thousandth of a millimeter, in diameter. Baker's research team is making major inroads in optimizing thefunction of computer-designed influenza inhibitors. These proteinsare constructed via computer modeling to fit exquisitely into aspecific nano-sized target on flu viruses. By binding the targetregion like a key into a lock, they keep the virus from changingshape, a tactic that the virus uses to infect living cells. Theresearch efforts, akin to docking a space station but on amolecular level, are made possible by computers that can describethe landscapes of forces involved on the submicroscopic scale. Baker heads the new Institute for Protein Design Center at theUniversity of Washington. Biochemists, computer scientists,engineers and medical specialists at the center are engineeringnovel proteins with new functions for specific purposes inmedicine, environmental protection and other fields. Proteinsunderlie all normal activities and structures of living cells, andalso regulate disease actions of pathogens like viruses. Abnormalprotein formation and interactions are also implicated in manyinherited and later-life chronic disorders. Because influenza is a serious worldwide public health concern dueto its genetic shifts and drifts that periodically become morevirulent, the flu is one of the key interests of the Institutes forProtein Design and its collaborators in the United States andabroad. Researchers are trying to meet the urgent need for bettertherapeutics to protect against this very adaptable and extremelyinfective virus. Vaccines for new strains of influenza take monthsto develop, test and manufacture, and are not helpful for thosealready sick. The long response time for vaccine creation anddistribution is unnerving when a more deadly strain suddenlyemerges and spreads quickly. The speed of transmission isaccelerated by the lack of widespread immunity in the generalpopulation to the latest form of the virus. Flu trackers refer to strains by their H and N subtypes. H standsfor hemagglutinins, which are the molecules on the flu virus thatenable it to invade the cells of respiratory passages. The virus'shemagglutinin molecules attach to the surface of cells lining therespiratory tract. When the cell tries to engulf the virus, itmakes the mistake of drawing it into a more acidic location. Thedrop in pH changes the shape of the viral hemagglutinin, therebyallowing the virus to fuse to the cell and open an entry for thevirus' RNA to come in and start making fresh viruses. It ishypothesized that the Baker Lab protein inhibits this shape changeby binding the hemagglutinin in a very specific orientation andthus keeps the virus from invading cells. Baker and his team wanted to create antivirals that could reactagainst a wide variety of H subtypes, as this versatility couldlead to a comprehensive therapy for influenza. Specifically,viruses that have hemagglutinins of the H2 subtype are responsiblefor the deadly pandemic of 1957 and continued to circulate until1968. People born after that date haven't been exposed to H2viruses. The recent avian flu has a new version of H1hemagglutinin. Data suggests that Baker's proteins bind to alltypes of the Group I Hemagglutinin, a group that includes not justH1 but the pandemic H2 and avian H5 strains. Recognizing the importance of new flu therapies to national andinternational security, the Defense Advanced Research ProjectsAgency and the Defense Threat Reduction Agency funded this work,along with the National Institutes of Health's National Institutefor Allergy and Infectious Diseases. The researchers also used theAdvanced Photon Source at Argonne National Laboratories inIllinois, with support from the Department of Energy, Basic EnergySciences. The methods developed for the influenza inhibitor protein design,Baker said, could be "a powerful route to inhibitors or binders forany surface patch on any desired target of interest." For example,if a new disease pathogen arises, scientists could figure out howit interacts with human cells or other hosts on a molecular level.Scientists could then use protein interface design to generate adiversity of small proteins that they predict would block thepathogen's interaction surface. Genes for large numbers of the most promising, computer-designedproteins could be tested using yeast cells. After further molecularchemistry studies to find the best binding among those proteins,those could be re-programmed in the lab to undergo mutations, andall the mutated forms could be stored in a "library" for anin-depth analysis of their amino acids, molecular architecture andenergy bonds. Advanced technologies would allow the scientists toquickly thumb through the library to pick out those tiny proteinsthat clung to the pathogen surface target with pinpoint accuracy.The finalists would be selected from this pool for excelling atstopping the pathogen from attaching to, entering and infectinghuman or animal cells. The use of deep sequencing, the same technology now used tosequence human genomes cheaply, was especially crucial in creatingdetailed maps relating sequencing to function. These maps were usedto reprogram the design to achieve a more precise interactionbetween the inhibitor protein and the virus molecule. It alsoenabled the scientists, they said, "to leapfrog over bottlenecks"to improve the activity of the binder. They were able to see howsmall contributions from many tiny changes in the protein, toodifficult to spot individually, could together create a binder withbetter attachment strength. "We anticipate that our approach combining computational designfollowed by comprehensive energy landscape mapping," Baker said,"will be widely useful in generating high-affinity andhigh-specificity binders to a broad range of targets for use intherapeutics and diagnostics." Timothy Whitehead and Aaron Chevalier, both members of the Bakerlab, led the flu inhibitor protein project. Whitehead is now atMichigan State University. Other researchers on the project wereYifan Song, Cyrille Dreyfus, Sarel J. Fleishman, Cecilia De Mattos,Chris A. Myers, Hetunandan Kamisetty, Patrick Blair and Ian Wilson. I am an expert from huatecgroup.com, while we provides the quality product, such as Portable Hardness Tester , Gloss Meters, X-ray Pipeline Crawlers,and more.
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