Computer-Designed Proteins Programmed to Deactivate Flu Viruses

Computer-designed proteins are now being constructed to fight the flu. Researchers are demonstrating that proteins found in nature, but that do not normally bind the flu, can be engineered to act as broad-spectrum antiviral agents against a range of flu virus strains, including H1N1 pandemic influenza.

“One of these engineered proteins has a flu-fighting potency that rivals that of several human monoclonal antibodies,” said Dr. David Baker, a professor of biochemistry at the University of Washington (Seattle, USA), in a report June 7, 2012, published in the journal Nature Biotechnology.

Dr. Baker’s research team is making major inroads in optimizing the function of computer-designed influenza inhibitors. These proteins are constructed via computer modeling to fit exquisitely into a specific nano-sized target on flu viruses. By binding the target areas similar to a key into a lock, they keep the virus from changing shape, a tactic that the virus uses to infect living cells. The research efforts, analogous to docking a space station but on a molecular level, are made possible by computers that can describe the panoramas of forces involved on the submicroscopic scale.

Dr. Baker is head of the new Institute for Protein Design Center at the University of Washington. Biochemists, engineers, computer scientists, and medical specialists at the center are engineering innovative proteins with new functions for specific purposes in medicine, environmental protection, and other areas. Proteins underlie all typical activities and structures of living cells, and also control disease actions of pathogens such as viruses. Abnormal protein formation and interactions are also implicated in many inherited and later-life chronic disorders.

Because influenza is a serious worldwide public health problem due to its genetic shifts and drifts that sporadically become more virulent, the flu is one of the key interests of the Institutes for Protein Design and its collaborators in the United States and worldwide. Researchers are trying to meet the vital need for better therapeutic agents to protect against this very adaptable and extremely infective virus. Vaccines for new strains of influenza take months to develop, evaluate, and manufacture, and are not helpful for those already sick. The long response time for vaccine creation and distribution is unsettling when a more lethal strain abruptly emerges and spreads rapidly. The speed of transmission is accelerated by the lack of widespread immunity in the general population to the latest form of the virus.

Flu trackers refer to strains by their H and N subtypes. H stands for hemagglutinins, which are the molecules on the flu virus that enable it to invade the cells of respiratory passages. The virus’s hemagglutinin molecules attach to the surface of cells lining the respiratory tract. When the cell tries to engulf the virus, it makes the error of pulling it into a more acidic location. The drop in pH changes the shape of the viral hemagglutinin, thereby allowing the virus to fuse to the cell and open an entry for the virus’ RNA to come in and start making fresh viruses. It is hypothesized that the Baker Lab protein inhibits this shape change by binding the hemagglutinin in a very specific orientation and thus keeps the virus from invading cells.

Dr. Baker and his team wanted to create antivirals that could react against a wide variety of H subtypes, as this versatility could lead to a comprehensive therapy for influenza. Specifically, viruses that have hemagglutinins of the H2 subtype are responsible for the deadly pandemic of 1957 and continued to circulate until 1968. People born after that date have not been exposed to H2 viruses. The recent avian flu has a new version of H1 hemagglutinin. Data suggest that Dr. Baker’s proteins bind to all types of the group I hemagglutinin, a group that includes not only H1 but also the pandemic H2 and avian H5 strains.

The methods developed for the influenza inhibitor protein design, according to Dr. Baker, could be “a powerful route to inhibitors or binders for any surface patch on any desired target of interest.” For example, if a new disease pathogen arises, scientists could figure out how it interacts with human cells or other hosts on a molecular level. Scientists could then employ protein interface design to create a diversity of small proteins that they predict would block the pathogen’s interaction surface.

Genes for large numbers of the most promising, computer-designed proteins could be tested using yeast cells. After additional molecular chemistry research to search for the best binding among those proteins, those could be reprogrammed in the laboratory to undergo mutations, and all the mutated forms could be stored in a “library” for an in-depth examination of their amino acids, molecular architecture, and energy bonds.

Sophisticated technologies would allow the scientists to rapidly browse through the library to find those tiny proteins that clung to the pathogen surface target with pinpoint accuracy. The finalists would be selected from this pool for excelling at blocking the pathogen from attaching to, entering, and infecting human or animal cells.

The utilization of deep sequencing, the same technology now used to sequence human genomes cheaply, was particularly central in creating detailed maps relating sequencing to function. These maps were used to reprogram the design to achieve a more exact interaction between the inhibitor protein and the virus molecule. It also enabled the scientists, they said, “to leapfrog over bottlenecks” to improve the activity of the binder. They were able to see how small contributions from many small alterations in the protein, too difficult to see individually, could together create a binder with better attachment strength.

“We anticipate that our approach combining computational design followed by comprehensive energy landscape mapping,” Dr. Baker said, “will be widely useful in generating high-affinity and high-specificity binders to a broad range of targets for use in therapeutics and diagnostics.”

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