Next generation of HIV drugs could be 70 times more effective with EFdA compound

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Taking any medicine long-term makes eventual drug resistance almost inevitable—but researchers at the Bond Life Sciences Center may have found the most potent antiretroviral yet.

A lab there was recently able to prove that the compound EFdA, which stops HIV from proliferating, can be up to seventy times more effective against HIV than Tenofovir, currently one of the drugs most commonly prescribed for people living with HIV/AIDS.

Bond LSC virologist Stefan Sarafianos said, “HIV in patients treated with Tenofovir eventually develop a K65R RT mutation that causes a failure of this first line of defense. Not only does EFdA work on resistant HIV, but it works ten times better than on wild-type HIV that hasn’t become Tenofovir resistant,” Decoding Science reported.

Sarafianos and a team of researchers also discovered that EFdA (4’-ethynyl-2-fluoro-2’-deoxyadenosine) is easier for cells to activate, and isn’t broken down as quickly by a patient’s liver and kidneys as similar drugs currently in use. He said, “These two reasons make it more potent than other drugs, and so our task is to look at the structural features that make it such a fantastic drug.”

The original breakthrough, in 2001, was by a different kind of science lab—a Japanese soy sauce company discovered EFdA while working on molecular flavor enhancers. They realized it was very similar to current HIV drugs, part of the compound family called nucleoside analogues, which was confirmed by testing. That started over a decade of research to learn EFdA’s secrets.

Specifically, EFdA is part of the compound class called nucleoside reverse transcriptase inhibitors (NRTIs), which is the same class as eight current HIV drugs. Sarafianos explained, “NRTIs are called chain terminators because they stop the copying of the DNA chain, and once incorporated it’s like a dead end.”

Bond LSC is also working closely with National Institutes of Health’s Hiroaki Mitsuya and University of Pittsburgh biochemist Michael Parniak to discover everything they can about EFdA’s potential. Mitsuya helped discover the first three antiretrovirals approved to fight HIV, and Parniak has been studying the effectives of various HIV treatments on white blood cells for years.

Together, the researchers are working to define how EFdA works on a molecular level, piecing together its exact structure and configuration. Sarafianos explained, “The structure of this compound is very important because it’s a lock and key kind of mechanism that can be recognized by the target. We’re looking at small changes and the ideal scenario is a compound bound very efficiently by the target and activating enzyme but not efficiently by the degrading enzymes.”

Early trials so far have been very promising. In 2012, a group of monkeys with SIV, the simian equivalent of HIV, responded extremely well to treatment with EFdA. Parniak said, “These animals were so lethargic, so ill, that they were scheduled to be euthanized when EFdA was administered. Within a month they were bouncing around in their cages, looking very happy and their virus load dropped to undetectable levels. That shows you the activity of the molecule; it’s so active that resistance doesn’t come in as much of a factor with it.”

EFdA is even showing potential as an HIV prevention tool. With the help of formulation expert Lisa Rohan from the University of Pittsburgh, the researchers are working on using EFdA in a vaginal film, the consistency of which is comparable to Listerine breath strips. Parniak explained, “The only way we are going to make a difference with HIV is prevention. If we can prevent transmission, this approach could make a huge difference in minimizing the continued spread of the disease when combined with existing therapies for people already infected.”

In the nations of sub-Saharan Africa, HIV/AIDS is most commonly seen in women, who account for more than 70 percent of new HIV patients. Gels and creams have more limited shelf lives than films, which could be of great benefit to those at high risk in third-world countries. In 2012, pharmaceutical giant Merck licensed the drug, and is currently finishing preclinical trials focused on HIV prevention.

Sarafianos said, “We have nearly 30 drugs approved for treating HIV infected individuals, but only one approved for prevention. Women in Africa would benefit from a formulation like this as a means to protect themselves.”

Not content to merely know that EFdA is highly effective against HIV, the researchers are determined to discover the secrets behind its effectiveness.

Parniak explained, “We want to understand how long EFdA stays in the bloodstream and cells. If we understand structurally why this drug is so potent it allows us to maybe develop additional molecules equally potent and a combination of those molecules could be a blockbuster.”

429Magazine

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