Researchers at Hopkins are changing the way that drug developers think about antiviral drug design and, in so doing, are making advances in the treatment of a strain of the HIV virus.
In a paper recently published in the journal Chemical and Biological Drug Design, a group of Hopkins biologists have introduced a "new paradigm" for the creation of effective antiviral drugs, according to Ernesto Freire, one of the authors of the paper.
"We had a very simple goal; to evaluate all the inhibitors that were being approved or under development and identify the characteristics that make some inhibitors good and some bad," Freire said.
Freire's research on HIV began around 10 years ago, but in the past two years his lab has been focusing on HIV-2, a strain of the HIV virus that infects between one and two million people worldwide.
In comparison, about 40 million people are infected with HIV-1, so all of the FDA-approved antiviral drugs on the market have been designed to target HIV-1 specifically. The relatively smaller population who have HIV-2 don't provide enough economic stimulus for drug companies to focus on HIV-2 therapies.
Because of the lack of treatments tailored to HIV-2, Freire's lab decided to investigate which existing antiviral drugs are most effective in treating HIV-2.
An inhibitor is a drug that blocks the maturation of a virus. HIV uses a protease enzyme to process its proteins and allow it to mature. A protease inhibitor stops this process from occurring and thus prevents the virus from reproducing.
Evan Brower, a graduate student who works in Freire's lab, did the actual testing of the HIV-1 drugs. "My direct role was to take the nine clinically approved inhibitors for HIV-1 protease and see how well they worked for HIV-2 protease," Brower said.
Brower described the analysis as the most challenging aspect of the work. After obtaining his results, it was very difficult to explain them. He ended up testing more than 250 possible variables, but found that one - a property of the inhibitor called cap size - was the most "inhibitory structural parameter," meaning that it has the biggest impact in the determination of an inhibitor's success against HIV-2.
Cap size refers to specific groups of atoms positioned on the inhibitor molecule that tailor the inhibitor to its target protein. A large and flexible cap means more possible rotation of bonds within the cap, which leads to an increased ability of the inhibitor to adapt to a mutating virus. The drugs with the largest cap are therefore the most effective in treating HIV-2.
A helpful way to understand an important aspect of drug design, Freire explained, is the "lock and key analogy," which says that if a virus is a lock, the inhibitor should be a key that fits perfectly in that lock. This view has recently been usurped, partially due to the lab's work.
"In the past, there was a dogma in drug design to make molecules that were very rigid, but a virus is able to change the lock, and if the key is rigid, it cannot adapt to the new lock. What we need is a master key that will open all locks," Freire said.
Freire listed three basic characteristics of a good inhibitor: "potency, selectivity and adaptability."
A potent inhibitor is powerful enough to keep the virus from creating more copies of itself. A selective inhibitor is singularly focused on its target, and an adaptable inhibitor can change with the virus as it mutates, while not losing the key components that allow it to function.
Freire's paper offers new insight on adaptability. "The research confirms that inhibitors that have elements that are able to adapt to changes are the ones that lose less potency when facing mutations," Freire said.
"The virus mutates when you take drugs, but the protease cannot mutate at will because it still has to work. Instead of something that is completely rigid all over, you have only specific rigid regions that target conserved parts of the protease."
Freire added that this set of three features that stemmed from this research on HIV forms "a drug development platform" that is being used to develop drugs to treat other viruses that have no cures, like Hepatitis C and Severe Acute Respiratory Syndrome (SARS).
Freire and his colleagues are proud that their findings will help patients with HIV-2 and are being applied to drug design in general. However, "there is always the frustration that despite all the research in labs all over the world, there is still no cure [for HIV]," Freire said.
