Ronald Zuckermann, director of the Molecular Foundry at Lawrence Berkeley National Laboratory, and his colleagues have created a two-dimensional sugar-coated nanosheet that mimics the surface of cells and, in doing so, can selectively target pathogens like viruses and bacteria.
Since its inception, the field of synthetic biology has tried to design and build cells, proteins, and other biological entities using the winning combination of synthetic polymers and the principles of sound engineering. Now, Ronald Zuckermann, director of the Molecular Foundry at Lawrence Berkeley National Laboratory, and his colleagues have created a two-dimensional sugar-coated nanosheet that mimics the surface of cells and, in doing so, can selectively target pathogens like viruses and bacteria.
Science has traditionally battled diseases with drug molecules, which are very small. Those molecules act like a single key that you would use to open one door that gives you access to the whole house. Nanosheets, on the other hand, provide access through many doors.
“These sheets don’t require a key, something with a specific and exact pattern that fits into only that front door lock,” Zuckermann says. “It’s more like wrapping the whole house in a fumigation tent—one that can protect the house from these invaders by detecting them or even inactivating them.”
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The foundation of this new technology are synthetic polymers known as peptoids. About 25 years ago, Zuckermann and his colleagues developed a method that allowed them to build a polymer one monomer at a time, programming chemical information into the material as they did so. The result was the “peptoid,” or the synthetic equivalent of the peptide, or chain of amino acids found in traditional biology. Zuckermann’s synthetic structures share the same architecture as biological structures.
“Now we understand a lot of the rules about the peptoids, and if we put this sequence here, it will form a nanosheet with a defined shape,” he says. “And then if we put this sequence there, it will form a little loop on the surface of that nanosheet. That’s what allows us to put the sugars on the top of the sheet, similar to what you see on the surface of a cell.”
One advantage of these nanosheets is that the peptoids can spontaneously self-assemble in water using fundamental attractive and repulsive forces found in physics. The nanosheets use a simple A-B pattern where every other group is hydrophobic (water-repelling); a pattern that Zuckermann admits his group stumbled upon by accident.
“About 8 years ago, we found this A-B pattern makes nanosheets. The breakthrough to make a sequence-defined polymer super-fast with super-efficient yields occurred 25 years ago. We already had that,” he explains. “So, with the ability to create this nanosheet, this blank slate, really, for us, the focus became, ‘What sequence can we make that assembles into something productive and useful?’”
It’s long been known that many pathogens, of both the viral and bacterial variety, infect cells by first binding to sugars naturally found on the cell surface. Zuckermann’s team engineered the peptoid-based nanosheets with patterns of simple sugars on the surface. They were then able to demonstrate that the sugars could then selectively bind with proteins associated with Shiga toxin, the bacteria responsible for dysentery. The results were published in the March 2018 issue of ACS Nano.
“Shiga isn’t the only pathogen that binds to sugars on cell surfaces, of course,” he says. “But if we select the right sugars and put them in the right distributions on the nanosheet, we should be able to attract any number of different pathogens.”
Scaling Up and Scaling Out
Zuckermann sees several potential applications for these nanosheets, ranging from a nasal spray that can help people avoid their annual bout with the influenza virus to a free-floating sheet that offers water filtration capabilities. He also says that the nanosheets can offer great sensing capabilities.
“There are a lot of ways to make a sensor chip coded with something that binds with a virus,” he says. “But people haven’t been able to make a free-floating little piece of biological flypaper in solution that specifically binds to a virus. This is something that we could deploy out into the wild—into an environmental spill site or topically on mucous membranes to see if there’s a particular pathogen there.”
While it will take some time to scale up and scale out this technology, Zuckermann is very optimistic. He says the peptoid technology is a strong basis for new development work: an undergrad can build one of these peptoids in a couple of days and they are incredibly stable in a variety of environments. It’s just a matter of designing the right nanosheets for the right applications.
“There’s no reason these nanosheets can’t be scaled up and made from pretty cheap building blocks. We’d like to see that happen in the next few years,” Zuckermann says. “But looking further out, we really want to understand the rules about how you can use this kind of technology to design a synthetic enzyme or antibody. The benefits are two-fold: proteins do all the important catalytic and structural work in our bodies so there are a ton of applications there. But, in addition, if we can understand the biology well enough to make a synthetic structure that works in the same ways, that means we also understand what makes the biology tick. That’s really the deeper, scientific motivation for what we’re doing here.”
Kayt Sukel is an independent technology writer based in Houston, TX.
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