The new drug target, which is known as a protease dimer, could serve as a model for developing new therapeutics for diseases ranging from cancer to Alzheimer’s, the researchers say. Findings are reported in the Advance Online Publication section of the Nature Chemical Biology web site.

Most current antiviral drugs target the active sites of viral proteins, where enzymes and receptors work in a lock-and-key approach to either activate or deactivate that particular protein, the researchers explained. Traditionally, drug development has focused on inhibiting that lock-and-key action to prevent the enzyme, or receptor from being effective.

Some viral enzymes known as proteases, however, including those for HIV and the herpes virus family, take the form of a dimer, or two identical halves – much like a fully opened clamshell – in their most stable state. Those proteases play an essential role in making the virus infectious, but require the two clamshell halves to bind together to be activated, according to the paper.

The HIV protease was successfully targeted for drug development in the 1980s, by blocking the active site on the surface of the dimer, but the herpes virus protease dimer has consistently eluded efforts to disrupt it at its active site, the researchers said.

The UCSF team set out to find ways to instead prevent the two halves of the dimer from connecting at that clamshell joint, to prevent it from activating. What they found was a new target on the unstable, monomer form of the protease, which responded well to a chemical inhibitor.

“If you disrupt the protein-protein interactions, you don’t need the key to a specific lock,” said Charles S. Craik, PhD, senior author on the paper and a professor of pharmaceutical chemistry in the UCSF School of Pharmacy. “Instead, we’re essentially preventing the lock from being made in the first place.”

Craik, who also led a team that identified HIV protease inhibitors in the late 1980s, said the “Nature Chemical Biology” paper validates this new site as a viable option for small-molecule drugs to treat Kaposi’s, as well as other members of this viral family.

“All known herpes virus proteases are structurally similar,” Craik explained. “The inhibitor we found knocks out not only KS, but also the cytomegalovirus protease, so the site we’ve identified here could be a target for a broad-acting inhibitor against the entire viral family.”

To their knowledge, the researchers said, this is the first small-molecule inhibitor of a herpes virus protease to not only act outside the active site, but also to select for the partially unfolded protein to keep it from forming the dimer interface.

Herpes viruses make up one of the most prevalent viral families, including eight human viruses that cause a variety of devastating illnesses, the researchers said. Those include mononucleosis (Epstein-Barr virus), shingles (Varicella zoster virus), genital herpes (herpes simplex), retinitis (cytomegalovirus) and cancer (Kaposi’s sarcoma). While therapies exist for these viruses, they often have negative side effects and are facing rising viral resistance.

In addition to validating herpes virus proteases as suitable targets, Craik said this research was also among the first to use computational design to identify and create a potential drug to target that protease interface.

Using high-throughput screening, the team screened a library of 182 compounds that it had specifically and rationally designed to mimic the protease interface. The work identified six molecules that inhibited the Kaposi’s sarcoma virus protease activity by at least 50 percent, including one that was highly potent.

That discovery potentially opens myriad opportunities for drug discovery, Craik said, by making target receptors that were biologically validated, but then deemed undruggable, more attractive. Protein-protein interactions have been researched as drug targets against a range of diseases, from certain cancers to neurodegenerative diseases. This advance could enable researchers to reconsider those targets, he said.

The lead investigator on the paper was Tina Shahian, with the Graduate Group in Biochemistry and Molecular Biology at UCSF. Co-authors were Gregory M. Lee and Ana Lazic, both in the UCSF Department of Pharmaceutical Chemistry; and Leggy A. Arnold, Priya Velusamy, Christina M. Roels and R. Kiplin Guy, all with the Department of Chemical Biology and Therapeutics at St. Jude Children’s Research Hospital, Memphis, TN.

The CMV protease expression plasmid for this work was provided by Wade Gibson, a professor in the Department of Pharmacology and Molecular Sciences at Johns Hopkins School of Medicine. The work was funded by grants from the National Institutes of Health, the American Lebanese and Syrian Associated Charities and St. Jude Children’s Research Hospital.

CORVALLIS, Ore.--Many people look for natural or green products for their homes. But even something as natural-looking as wood furniture or cabinets can contain cancer-causing chemicals like formaldehyde. Now, a scientist has created a non-toxic wood adhesive. And his inspiration didn't come from the forest. It came from the Oregon coast.

Pounding waves are no match for the mighty mussel, that produces strong, flexible threads that cling to rocks. This small shellfish inspired a big idea for wood chemist Kaichang Li.

"This thing is really amazing," Li, of Oregon State University in Corvallis, tells DBIS. He noticed mussels secrete a unique amino acid called dihydroxyphenylalanine. He found a way to add that amino acid to soy flour -- a product that's rich in protein, plentiful and non-toxic.

"Now the soy protein becomes a really good, very strong adhesive," Li says, wood glue so strong that plywood made with it stays stuck even after hours of boiling.

Oregon State University licensed the new glue to a plywood manufacturer who then sells the wood to furniture and cabinet makers.

Rick Fields, President of Neil Kelly Cabinets in Portland, Ore., says: "We're very excited about it. It's going to add a whole new dimension to our green and healthy approach to cabinet making." He is confident the new glue is safer for customers and says it shouldn't add to the cost of the cabinets.

"If you'd asked me a year ago whether this was possible, I would have said, 'No,'" said study co-author James McNew, associate professor of biochemistry and cell biology at Rice University. "In fact, that's exactly what I told (co-author) Andrea Daga when we first spoke about the idea a year ago."

McNew has spent the past 15 years studying SNARE proteins, a specialized family of proteins that carries out membrane fusion. It's a vital process that happens thousands of times a second in every cell of our bodies.

"It is fitting that the discovery of a new protein capable of fusing membranes comes 10 years after the demonstration that SNAREs can fuse lipid bilayers," said Daga, a researcher at the Eugenio Medea Scientific Institute in Conegliano, Italy.

In the new study, Daga's and McNew's research teams used fruit flies to study how atlastin functions. The atlastin in fruit flies is very similar to the human version of the protein and serves the same function.

"Prior to this, there were only two defined ways in which you could take biological membranes and put them together in a specific way," said McNew, a faculty investigator at Rice's BioScience Resesarch Collaborative. "Atlastin is the third, and it's the only one that requires enzymatic activity, so it's distinctly different."

Using a range of tests on purified proteins, live fruit flies and cell cultures, the Italian and U.S. teams examined the effect of both an overabundance and a scarcity of atlastin on cell function and on fruit fly development. They also created mutant versions of the protein to see how it functioned -- or failed to function -- when some parts were disabled.

The tests showed that cells with extra atlastin had an overdeveloped endoplasmic reticulum (ER), a system of interconnected membrane tubes and chambers that's critical for normal cell function. The tests also showed too little atlastin led to a fragmented ER. Flies with defective atlastin were sterile and short-lived.

"The endoplasmic reticulum is an ever-changing environment," McNew said. "It grows. It retracts. It expands. It collapses. It's highly dynamic, and for that to be the case, there has to be a mechanism by which it can grow new pieces and connect those pieces together. That's where the fusion comes in."

Daga said the discovery will lay the foundation for a deeper understanding of both basic biological processes and disease.

"We hope the findings lead to a better understanding of hereditary spastic paraplegia (HSP), the genetic disorder that atlastin has been linked with," Daga said.

HSP is a rare genetic condition that affects fewer than one million people worldwide. It's marked by a partial paralysis of the lower extremities due to defects in the body's longest cells, the neurons that run from the spine through the legs.

Daga said atlastin's role in building and maintaining a healthy ER may help HSP researchers better understand why neurons are affected first.

"This is the first clue," Daga said. "We have the definition of what the protein does. Now we need to explore how it does that, and what it means."

Co-authors include Genny Orso, Diana Pendin, Jessica Tosetto and Andrea Martinuzzi, all of Eugenio Medea Scientific Institute; Song Liu, Tyler Moss and Joseph Faust, all of Rice; Anastasia Egorova of Consorzio Mario Negri Sud in Santa Maria Imbaro, Italy; and Massimo Micaroni, now of the University of Queensland in Brisbane, Australia.