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Researchers develop antidote for poisonous digoxin

<p>Sagar Khare, a professor in the Department of Chemistry and Chemical Biology, along with his research team, came up with an antidote for digoxin, a cardiac drug lethal in high doses.</p>

Sagar Khare, a professor in the Department of Chemistry and Chemical Biology, along with his research team, came up with an antidote for digoxin, a cardiac drug lethal in high doses.

In 2003, the “Angel of Death” Charles Cullen admitted to the murder of 40 hospital patients across New Jersey and Pennsylvania.

Cullen, a former nurse, used the cardiac drug digoxin as his weapon to commit his crimes over a period of 16 years.

Ten years later, a team of Rutgers and University of Washington chemists has developed an antidote to the poisonous drug.

In a “Nature” paper entitled “Computational Design of Ligand Binding Proteins with High Affinity and Selectivity,” the chemists introduce DIG10.3, a protein that binds to, and therefore inhibits, digoxin.

DIG10.3 binds to the digoxin molecule as tightly as a glove fits a hand, said Sagar Khare, co-author of the paper.

“It’s a lock-and-key mechanism,” said Khare, a professor in the Department of Chemistry and Chemical Biology.

Khare said his team decided to design the drug because of digoxin’s narrow therapeutic window.

“The difference between a therapeutic dose and an overdose is very small,” he said.

Even if a patient lives from digoxin poisoning, he said, the drug commonly causes side effects including visual disturbances like seeing halos and intense shades of yellow.

Khare said post-impressionist painter Vincent Van Gogh was an example of a person who saw images patients would see while on the drug.

Scholars speculate Van Gogh received digoxin-rich foxglove plant to treat his epilepsy, Khare said, referring to an article published in the Journal of American Medical Association. Van Gogh’s paintings, including his famous work “Starry Night,” feature intense yellow halos.

With this anecdote and the murders by Cullen, Khare said the atmosphere was right for focusing the researchers’ efforts on digoxin.

Khare said currently, proteins called antibodies exist in the blood to chemically combine toxins like digoxin, but they are difficult to make and test for scientific use because they require animal subjects.

He said other proteins are a cheaper and more effective alternative to the antibodies.

“There was a high medical need for an antidote,” he said.

The most exciting part of the team’s method, though, is its generality. Khare said the team could theoretically develop a protein to bind to any molecule.

“They are made-to-order,” he said.

The team began their design with a molecular model of the protein, said co-author Jorgen Nelson, a third-year graduate student at the University of Washington. The model determines which amino acid components of the protein the team needs to replicate.

Once the team knows which amino acids to use, Nelson said, the researchers input the data into software called Rosetta, developed in co-author David Baker’s laboratory at the University of Washington.

According to its website, Rosetta models intra-molecular and intermolecular interactions to predict the shape of proteins in nature.

Christine Tinberg, a post-doctoral fellow in Baker’s laboratory, said the program begins by matching the team’s data with a protein listed in the Protein Data Bank, an online repository for information about the 3D structures of proteins and other organic molecules.

Once the program produces a shape the team finds desirable, the team purchases DNA to grow the proteins in bacteria. They then extract the protein and test how well it binds to target molecules, like DIG10.3 did with digoxin, she said.

She said the team took almost two years to develop the version of DIG10.3 featured in the paper. The protein binds almost perfectly to digoxin.

Now, the team is working with the researchers in the laboratory of Charalampos Kalodimos, a professor in the Department of Chemistry and Chemical Biology, to understand how the binding occurs.

Khare said understanding the mechanism will make Rosetta’s algorithm more accurate, producing better binders.

The team is also continuing improvement on DIG10.3. Their next goal is to develop the protein into a sensor for disease indicators, Tinberg said.

She said the team’s method could solve problems beyond medicine.

“The proteins could even be used as bioscavengers, soaking up toxins from the environment,” she said.

Nelson shared Tinberg’s hope. He said this method could become a mainstream solution to drug design and beyond.

“Given the amazing variety of roles proteins fill in the natural world, I think there’s very little we shouldn’t eventually be able to do with them,” he said.

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