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.
This shows a model of the "threading tetra-intercalator" bound up in the double helix of a DNA sequence. Credit: Brent Iverson
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.
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.
Daniel Oppenheimer | EurekAlert!
Scientists unlock ability to generate new sensory hair cells
22.02.2017 | Brigham and Women's Hospital
New insights into the information processing of motor neurons
22.02.2017 | Max Planck Florida Institute for Neuroscience
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
22.02.2017 | Power and Electrical Engineering
22.02.2017 | Life Sciences
22.02.2017 | Physics and Astronomy