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A hunch leads to an anti-HIV compound

Yale Medicine Magazine, 2016 - Winter


A sponge, a protein, and a new way to thwart HIV infection.

What if there were a natural compound that could prevent HIV infection without damaging living cells? Batzelladine B is such a compound. It was discovered in the late 1990s in the red sponge from the Caribbean. But the process of synthesis, or recreating it in the lab, proved complex and lengthy. Seth Herzon, Ph.D., professor of chemistry and pharmacology, whose lab focuses on natural product synthesis, recently discovered a new and efficient route for synthesizing batzelladine that makes it more readily available for HIV-related research. With the shorter synthesis comes the ability to modify the structures of batzelladine more easily and make improved derivatives with better properties.

Batzelladine’s advantage is that it blocks the HIV protein GP120 as it tries to bind with CD4 receptors on the membranes of immune system T cells. Once the protein binds, the virus then injects its genomic information into the cell where it replicates, bursting the T cell and spreading infection. Batzelladine binds to the T cell’s CD4 receptors and prevents the HIV protein from fusing to the cell membrane.

Herzon’s team, which included postdoctoral associate Brendan Parr, Ph.D., and graduate student Christos Economou, hoped to find a faster way of synthesizing batzelladine. One hurdle was that batzelladine contains nitrogen, an element with conflicting attributes. It helps compounds interact with biological systems, but it can also be unpredictable—requiring extra steps to temper its reactivity. So the team used stable ringed compounds called pyrroles as the molecular starting point. “Making this connection allowed us to develop a very short route that used about half of the steps other people have needed to create similar structures,” Herzon explained.

Throughout the process Parr and Economou worked through each reaction and then met with Herzon to brainstorm changes. “We began with what we thought would happen and then ran the reaction. But as is common in synthesis, what we thought would happen usually didn’t occur,” said Herzon. “First, we had to understand what had happened. Then, we tried to adjust how we were thinking about the structure in order to think of new reactions that might do what we wanted them to do.” For example, batzelladine consists of two fragments. While the first fragment was created quickly, it took eight or nine approaches to the second fragment before finding one that worked.

Just as no plan of battle survives the first shot, experiments require some artistic capacity and intuition. “It takes a bit of faith, and willingness to go on your hunches,” he said. For example, they had a hunch that they could control nitrogen’s unpredictable nature until the last step in the plan. This allowed them to consolidate 10 discrete chemical reactions into a single step. “We didn’t initially plan this,” Herzon said. “But as the synthesis evolved we recognized that [multiple reactions] were possible and we were able to go for it.”

Once the synthetic plan was solidified, it was important to ensure that each step and reaction yielded the maximum amount of the chemical building block for the next step in the process. Though time-consuming, this phase resulted in a synthesis that requires only 15 steps and provides a good quantity of batzelladine.

The project took about 18 months; batzelladine can now be synthesized in about two weeks. This September, an interdisciplinary team, headed by Karen Anderson, Ph.D., professor of pharmacology and of molecular biophysics and biochemistry, began conducting further HIV research on batzelladine.

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