Duke Biochemists Create Animation of Cells' Drug Transporters
July 31, 2017
Researchers from Duke University School of Medicine have created a detailed illustration of how an important class of drugs pass into cells.
The drugs, called nucleoside analogs, treat a wide range of diseases — HIV, herpes, hepatitis, cancer, etc. — and the illustrations, published in the journal Nature, could lead to drugs that can be better designed to pass into cells and do the work they need to do.
Nucleoside analogs mimic the building blocks of DNA, which are called nucleosides. Each strand of DNA is made up of billions of these building blocks, so cells are always on the lookout for new ones to incorporate into DNA strands.
Each nucleoside analog has extra molecules attached to work inside the cell when the analog gets incorporated into the DNA. The analogs can cause DNA or the enzymes that help replicate DNA, which helps fight viruses that rely on this machinery to reproduce. The analogs can also signal cells to kill themselves, which is a useful tool to fight both viruses and cancer cells, both of which rapidly reproduce and therefore require lots of DNA.
Marscha Hirschi, a graduate biochemist at Duke and lead author of the study, wanted to study nucleoside transporters, the proteins responsible for pulling the analogs into the cell. A specific molecule, called the concentrative nucleoside transporter (CNT), changes its shape and moves nucleosides and nucleoside analogs through the cell membrane step by step.
Hirschi and her colleagues wanted to determine the exact structure of CNT and how it changes its shape to carry nucleoside analogs. The most powerful tool for determining chemical structures is a technique called X-Ray crystallography. Chemists take a dissolved chemical and solidify it into a crystal. They then shoot X-rays at the crystal and based on how they bounce off, they can determine the exact position of every atom in the molecule.
In order to get a complete step-by-step picture of how the CNT protein works, Hirschi and her colleagues isolated CNT from bacteria and crystallized it at every stage of its work in moving the nucleoside analog through the cell membrane. They compiled the images into a video that you can watch here.
The structure of the concentrative nucleoside transporter and the ways it folds itself could have broad-reaching consequences for antiviral and anti-cancer drugs. Knowing how the pieces fit together could allow drug-makers to design analogs that can more efficiently find their way into cells. They could also tailor analogs to fit best into specific cells, like ones that are infected with viruses or cancer cells.
Nucleoside analog medicines help millions of Americans each year, and this research could help make those medicines even more effective.
Daniel Lane covers science, medicine, engineering and the environment in North Carolina.