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Aug 4, 2014

Askew but Stable Metallohelices Self-Assemble, Fight Cancer

Askew but Stable Metallohelices Self-Assemble, Fight Cancer

The small organic units self-assemble and fold together around a metal ion [Fe(II)] in a similar manner to amphiphilic peptide alpha-helices. The helix this formed selectively targets cancer cells. [U Warwick]

  • They have shown promise as antimicrobials and anticancer drugs, but they are costly to manufacture. Worse, they are quickly neutralized by the body’s defenses. These drug candidates are cationic amphiphiles, small α-helical peptides that have an affinity for both water and lipids. They are designed to burrow into (and disrupt) cytoplasmic membranes.

    While cationic amphiphiles have attracted research interest, they have been a source of frustration, too, for not only are they expensive and short-lived, they also tend to be highly symmetric. They are, in many cases, the product of systems that offer little scope to tailor structure. With such systems, it is difficult to target specific biomolecules or to create libraries for phenotypic screens.

    A new system, however, takes a different approach. Instead of traditional peptides, it creates peptide mimics—asymmetric triplex metallohelices. These structures, which have a three-dimensional helical form similar to that of natural peptides, are being developed by researchers at the University of Warwick. In addition to being easy to produce—they spontaneously click together in a self-assembly process—they appear to have anticancer properties.

    The researchers, led by Peter Scott, Ph.D., gave an account of their work in the August 3 online issue of Nature Chemistry, in an article entitled “Asymmetric triplex metallohelices with high and selective activity against cancer cells.”

    “We report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices,” the authors wrote. “Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defense peptides and p53.”

    “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,” said Professor Scott. “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.”

    The molecules produced in the research have proved effective against colon cancer cells in laboratory tests. In particular: “The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 p53++, causing dramatic changes in the cell cycle without DNA damage.”

    And yet, despite this activity, the molecules appeared to have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468). Most remarkably, they showed no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. “This is very unusual and promising selectivity,” noted Professor Scott.

    Describing the self-assembly process, Professor Scott said: “When the organic chemicals involved, an amino alcohol derivative and a picoline, are mixed with iron chloride in a solvent, such as water or methanol, they form strong bonds and are designed to naturally fold together in minutes to form a helix. It’s all thermodynamically downhill. The assembly instructions are encoded in the chemicals themselves.”

    “Once the solvent has been removed we are left with the peptide mimics in the form of crystals,” continued Professor Scott. “There are no complicated separations to do, and unlike a Lego model kit there are no mysterious bits left over.”


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