This shows a model of the “threading tetra-intercalator” bound up in the double helix of a DNA sequence. Credit: Brent Iverson |
Chemists
at The University of Texas at Austin have created a molecule that’s so
good at tangling itself inside the double helix of a DNA sequence that
it can stay there for up to 16 days before the DNA liberates itself,
much longer than any other molecule reported.
It’s
an important step along the path to someday creating drugs that can go
after rogue DNA directly. Such drugs would be revolutionary in the
treatment of genetic diseases, cancer or retroviruses such as HIV, which
incorporate viral DNA directly into the body’s DNA.
“If
you think of DNA as a spiral staircase,” says Brent Iverson, professor
of chemistry and chair of the department of chemistry and biochemistry,
“imagine sliding something between the steps. That’s what our molecule
does. It can be visualized as binding to DNA in the same way a snake
might climb a ladder. It goes back and forth through the central
staircase with sections of it between the steps. Once in, it takes a
long time to get loose. Our off-rate under the conditions we used is the
slowest we know of by a wide margin.”
Iverson says the goal is to be able to directly turn on or off a particular sequence of genes.
“Take
HIV, for example,” he says. “We want to be able to track it to wherever
it is in the chromosome and just sit on it and keep it quiet. Right now
we treat HIV at a much later stage with drugs such as the protease
inhibitors, but at the end of the day, the HIV DNA is still there. This
would be a way to silence that stuff at its source.”
Iverson, whose results were published in Nature Chemistry
and presented this month at a colloquium at NYU, strongly cautions that
there are numerous obstacles to overcome before such treatments could
become available.
The
hypothetical drug would have to be able to get into cells and hunt down
a long and specific DNA sequence in the right region of our genome. It
would have to be able to bind to that sequence and stay there long
enough to be therapeutically meaningful.
“Those
are the big hurdles, but we jumped over two of them,” says Iverson.
“I’ll give presentations in which I begin by asking: Can DNA be a highly
specific drug target? When I start, a lot of the scientists in the
audience think it’s a ridiculous question. By the time I’m done, and
I’ve shown them what we can do, it’s not so ridiculous anymore.”
In
order to synthesize their binding molecule, Iverson and his colleagues
begin with the base molecule naphthalenetetracarboxylic diimide (NDI).
It’s a molecule that Iverson’s lab has been studying for more than a
decade.
They then piece NDI units together like a chain of tinker toys.
“It’s
pretty simple for us to make,” says Amy Rhoden Smith, a doctoral
student in Iverson’s lab and co-author on the paper. “We are able to
grow the chain of NDIs from special resin beads. We run reactions right
on the beads, attach pieces in the proper order and keep growing the
molecules until we are ready to cleave them off. It’s mostly automated
at this point.”
Rhoden
Smith says that the modular nature of these NDI chains, and the ease of
assembly, should help enormously as they work toward developing
molecules that bind to longer and more biologically significant DNA
sequences.
“The
larger molecule is composed of little pieces that bind to short
segments of DNA, kind of like the way Legos fit together,” she says.
“The little pieces can bind different sequences, and we can put them
together in different ways. We can put the Legos in a different
arrangement. Then we scan for sequences that they’ll bind.”
Iverson
and Rhoden Smith’s co-authors on the paper were Maha Zewail-Foote, a
visiting scientist in Iverson’s lab who’s now an associate professor and
chairman of chemistry at Southwestern University in Georgetown; Garen
Holman, another former doctoral student of Iverson’s who did most of the
experimental work before obtaining his Ph.D.; and Kenneth Johnson, the
Roger J. Williams Centennial Professor in Biochemistry at The University
of Texas at Austin.
