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Meet the 'Lego Death Star' Designed to Kill Cancer Dead

Self-assembling molecules promise to fortify the body's natural anti-cancer defenses.

It would be nice if there were some molecule or compound that just knew when something cruising around the human body was up to bad shit. That thing could be a clump of fungi, virulent bacterium, virus, or even a cancer cell, and our omnipotent friend would be all over it, tearing the invader apart limb from limb, at least in microorganism terms.

The human body, and really all kinds of life, produces just such a thing in the form of antimicrobal peptides, sub-protein molecules comprised of a linkage of amino acids and forming a variety of interesting shapes: helices, sheets, hairpins or loops, and just plain strings. Yet despite the body's production of such defenses, it's still capable of losing battles as peptides and other immune defenses become neutralized or overwhelmed.


But what if we could rearm the body with additional lines of peptide-based or peptide-similar defenses? This is the potential of new research out from a team based at the University of Warwick describing a method of pseudo-artificially producing defensive molecules that self-assemble once introduced into the body.

`In essence, it may be possible to deliver a batch of raw materials via a pill or whatever, which come together only once they're on the battlefield, forming into what's known as "peptide-mimetics," or structures that behave like peptides but are made of entirely different materials.

Of particular interest are helix-shaped peptides, which have the ability to penetrate the outer membranes of cells to all kinds of damaging effects. Once inside the target cell, a peptide may bind with different materials that cell needs to survive, interfere with its ability to make new proteins or DNA, destroy cellular membrane/walls from the inside-out, and-or increase production of the enzyme autolysin, which has the helpful effect of breaking apart the building blocks of biological cells and tissues. Some effects are even still unknown.

So peptide-mimetics are a very active site of medical research, and one such product is known as a helicate, a synthetic helix structure involving metal ions and complicated molecular knots. The current paper, published in Nature Chemistry, notes that "most helicates contain little if any external functionality, are incompatible with water, and are not readily available in an enantiomerically pure form."


Meanwhile, it turns out that whipping up batches of artificial "traditional" peptides doesn't work so well either.

"You can make them, but this is a laborious process and very expensive," Peter Scott, the study's lead author, told me. "Also, the lifetime of this kind of drug in the body is low, so it is destroyed by the body before it can do the therapeutic job."

So we're left with the goal of making something quite different from the body's version of protective peptides, while having the same basic effect.

Courtesy of Peter Scott/University of Warwick

"In nature, helical peptides are used for many, many jobs, and the activity of such a peptide against microbes or tumor cells depends on several things like the dimensions, the charge, and what is known as amphipathic architecture, [or] the placement of specific recognition elements on one side of the helix [see figure above] while the other side is pretty much unfunctionalised," said Scott. "We have been able to make things about the right size, with the right kind of charge, and that are amphipathic like the natural systems.

"The chemistry involved is like throwing Lego blocks into a bag, giving them a shake, and finding that you made a model of the Death Star," Scott added in a Warwick press release. "The design to achieve that takes some thought and computing power, but once you've worked it out the method can be used to make a lot of complicated molecular objects."

So far, the "Lego Death Stars" have been highly effective against colon cancer cells, while not having very much effect against bacterium. That's not as bad a thing as it might sound: Working against one and not the other suggests a more subtle operation at work and perhaps the promise of a bit more light on the defensive peptide world in general.

"A subtle biomimetic mechanism rather than broad-spectrum cytotoxicity is thus indicated, and this is corroborated by the observation of major changes to the cell cycle without detected DNA damage," the paper explains.

"The antimicrobial and anticancer peptides that the body makes, like those present in Cathelicidin and p53 are exquisite things that have evolved of billions of years," Scott says, "and we can't claim to have that sort of architecture here," but the architecture matches at least crudely, and that's what appears to matter.