SOP Reports Three High-Impact Studies about Molecular Workings of Disease

The prestigious journal Proceedings of the National Academy of Sciences published three separate School of Pharmacy studies aimed at designing better-targeted drugs to fight deadly bacterial diseases and liver cirrhosis.

By Steve Berberich
April 24, 2012

In late March, the top-tier journal Proceedings of the National Academy of Sciences published three separate studies led by researchers of the University of Maryland School of Pharmacy, each reporting significant discoveries that could pave the way to new therapeutic drug targets.

“These latest papers highlight the growth and excellence in the School’s Department of Pharmaceutical Sciences,” says Natalie D. Eddington, PhD, FAAPS, FCP, professor and dean. “Our faculty have the expertise to take such research from the initial mapping of the molecules to designing and testing drug candidates through clinical trials in collaboration with the other professional schools on the Baltimore campus of the University of Maryland.”

In one study, associate professor Patrick Wintrode, PhD, and colleagues provide insight into the molecular basis of alpha-1 antitrypsin deficiency, a disease that can lead to liver cirrhosis and emphysema. Antitrypsin deficiency affects about 200,000 people about in the United States. It is also under diagnosed because the disease is not routinely screened.

The disease is caused by a protein mutation at a single-point in its structure as the protein fails to fold properly.

“Our study is the first to employ a recently developed mass spectrometry technique to take ‘snapshots’ of antitrypsin as it folds into its correct shape,” says Wintrode. “We were able to ‘see’ the intermediate form of the molecule and determine which parts are correctly folded and which are not. This provides clues to how polymers form and which regions of the molecule should be targeted for drug design,” says Wintrode.

In the second PNAS paper, professor Angela Wilks, PhD, and colleagues unravel how gram negative bacteria such as Pseudomonas aeruginosa, a leading cause of hospital-acquired infections and a prominent infection in burn and trauma victims, take up and utilize iron from the human host. Specifically, pathogenic bacteria have adapted to utilize heme (a major iron containing molecule found in hemoglobin) as a source of iron.

In this study, Wilks and colleagues provide insight into the conformational changes required for interaction of an intracellular heme trafficking protein with the enzyme heme oxygenase. “This work defines a molecular mechanism that will allow us to develop inhibitors that disrupt delivery of heme to an enzyme critical to releasing iron to the bacteria.” Wilks and her colleagues in earlier publications have shown heme oxygenase is essential for virulence and a viable drug target.

“We believe that these studies give us the opportunity to target bacterial heme utilization with novel antimicrobials at various stages. This system is essential for virulence, and we envision by tipping the balance of iron in favor of the host and away from the pathogen we can combat bacterial infection. The fact that we are targeting a pathway essential for virulence but not survival outside of the host may lead to less selective pressure on the bacterium to develop antimicrobial resistance.”

The third PNAS paper by Sarah Michel, PhD, an associate professor, and Edwin Pozharski, PhD, an assistant professor, determines how the virulent bacterium Helicobacter pylori coordinates the use of nickel in regulating expression of certain genes. This bacterium causes gastric ulcers, which can lead to gastric cancers by colonizing the stomach lining of humans.

“In this paper, we present crystal structures and spectroscopic data for a key protein, NikR, which is required for Helicobacter pylori colonization. Our work reveals that nickel ions are key factors in this protein’s function,” says Michel. “We were able to propose a mechanism for nickel-mediated gene regulation by NikR that sets the stage for the design of inhibitors to target Helicobacter pylori infection, and subsequently gastric ulcers and gastric cancers.”

The Michel team collaborated with a group at the Stanford Synchrotron Radiation Lightsource in Menlo Park, Calif., to use a sophisticated technique called Small Angle Xray Scattering.

Titles of the three PNAS published studies aimed toward new drugs for serious infections are:

• “Folding mechanism of the metastable serpin alpha-1 antitrypsin”
• “Induced fit on heme binding to the Pseudomonas aeruginosa cytoplasmic heme binding protein (PhuS) drives interaction with heme oxygenase (HemO)”
• “Ni(II) coordination to mixed sites modulates DNA binding of HpNikR via a long range effect”