team of researchers at Duke University has determined the structure of a
key molecule that can carry chemotherapy and anti-viral drugs into
cells, which could help to create more effective drugs with fewer
effects to healthy tissue.
the structure and properties of the transporter molecule may be the key
to changing the way that some chemotherapies, for example, could work
in the body to prevent tumor growth,” said senior author Seok-Yong Lee,
Ph.D., assistant professor of biochemistry at Duke.
The article was published in Nature online on March 11.
transporter molecule, called a concentrative nucleoside transporter,
works by moving nucleosides, the building blocks of DNA and RNA, from
the outside to the inside of cells. It also transports nucleoside-like
chemo drugs through cell membranes. Once inside the cells, the
nucleoside-like drugs are modified into nucleotides that are
incorporated into DNA in ways that prevent tumor cells from dividing and
discovered the structure of the transporter molecule, and now we
believe it is possible to improve nucleoside drugs to be better
recognized by a particular form of the transporter molecule that resides
in certain types of tissue,” Lee said. “Now we know the transporter
molecule has three forms, which recognize different drugs and reside in
team determined the chemical and physical principles a transporter
molecule uses to recognize the nucleosides, “so if you can improve the
interactions between the transporter and the drug, you won’t need as
much of the drug to get it into the tumor cells efficiently,” Lee said.
“Knowing the shape of the transporters will let scientists design drugs
that are recognized well by this transporter.”
the drugs enter healthy cells as well as tumor cells, giving a lower
dose of drug that targets tumor tissue would be the best scenario, said
Lee, who is also a member of the Duke Ion Channel Research Unit.
“Healthy cells don’t divide as often as tumor cells, so lowering the
amount of drug given overall would be an effective approach to killing
tumors while protecting patients.”
researchers studied transporter molecules from Vibrio cholera, a
comma-shaped bacterium. The bacterial transporter serves as a good model
system for studying human transporters because they share similar amino
acid sequences. They found that both the human and bacterial
transporter use a sodium gradient to import nucleosides and drugs into
next step will be to try to understand which features of the
transporter confer the ability to recognize certain chemo drugs and
ultimately to design drugs that can easily enter the cells.
work won a prize for Dr. Lee, the National Institute of General Medical
Sciences Award, which he will receive at the Biophysical Society
meeting in February.
work was funded by the McKnight Endowment Fund for Neuroscience, the
Alfred P. Sloan Foundation, the Klingenstein Fund, the Mallinckrodt
Foundation, the Basil O’Connor Starter Scholar Research Award from the
March of Dimes Foundation, and the N.I.H. Director’s New Innovator
Award, in addition to start-up funds from the Duke University Medical
authors include Zachary Lee Johnson and Cheom-Gil Cheong also of the
Department of Biochemistry and the Ion Channel Research Unit.