Assistant Professor Deidre Johns specializes in synthesizing new drug therapies.
Gonorrhea infects 100 million new people every year. Here’s the really scary part: the disease is becoming resistant to third-generation antibiotics. According to the World Health Organization “Gonorrhea may soon become untreatable, as no vaccines or new drugs are in development. It is an increasingly serious threat to global public health.”
Assistant Professor Deidre Johns, OSU College of Veterinary Medicine, is collaborating with Assistant Professor Aleksandra Sikora, OSU College of Pharmacy, to identify targets for the development of new therapies for Gonorrhea.
The bacteria that causes Gonorrhea, N. gonorrhoea, has been particularly adept at mutating to resist treatment, so Johns and Sikora are working on a new approach with unique modes of action. Specifically, Johns is designing compounds that can interact with, and possibly inhibit, extracellular proteasome, a protein complex that forms in the outer membrane of bacteria.
Proteins are very large, complex molecules consisting of chains of amino acids. They can interact with other substances at specific locations known as binding sites. Johns is designing analogs, a series of small-molecule compounds whose structure makes them likely candidates for binding with, and inhibiting, these proteins. “Looking at the crystal structure gives me a 3-D picture of the pocket where I want the small molecule to interact with the protein,” she says. “So I look at the amino acid residues in that pocket and that guides me as to what kind of functional groups would have a favorable interaction. You also want the shape of the small molecule to fit the pocket.” Once she has the analogs designed, Johns will create compounds via chemical synthesis. Then Sikora will test the compounds for activity against the protein target.
Johns is proposing to design 200 compounds, but may not have to synthesize that many. “It takes me a little while to prepare each one,” she says, “so I’ll make a few, they’ll test them and we’ll learn from those. We might find that some of those 200 do not work, so we won’t go in that direction,” says Johns. “We will work very closely together, go back and forth, and Sikora’s insights from running the assay can inform the design of the next generation of compounds.”
Once Johns and Sikora have identified compounds that effectively interact with the protein, they can test them on the bacteria that causes Gonorrhoea. If any of them kill the bacteria, then the next step would be testing them on infected mice. “But, for now, we are looking at the protein to get better inhibitors before we go into the pathogen itself, because once you do that, you become concerned with many other factors that can occur. So first we take those variables away and just look at the protein.”
As an undergraduate at the University of California, San Diego, Johns majored in chemistry. “I started out liking inorganic chemistry,” she says, “then I realized I wanted to make compounds, so I went into synthetic organic where you make the most complicated thing possible. That was cool, but I realized I would rather spend my efforts on something that is not just going into the freezer. That is how I got into medicinal chemistry and drug discovery.”
After earning a PhD at the University of Colorado, Johns went on to work as an American Cancer Society Fellow at Colorado State University where she synthesized a natural product called FK228, which is now sold under the name Istodax, and used to treat cutaneous T-cell lymphoma.
What is on the horizon for her next?
“I would like to continue building a fragment library,” she says. Fragments are small portions of typical drug-sized molecules; Johns wants to build a collection of these to test against different proteins that might be good targets for new therapies. Unlike the typical drug development process that identifies active compounds, but then finds that many of them are too big to be useful, Johns wants to work in the opposite direction. “The idea is that the binding pockets in these proteins only accept certain shapes of molecules, so if a molecule is too big, maybe one part is good and the other part is blocking it from getting in. Maybe I can make something really small that can go in, and explore different binding modes; it can twist and turn, and bind where it wants to because it is so small. I think it is a really efficient way of designing drugs.”
