Millipede chemistry could unlock the secret to defeating brain disease

Millipedes aren't perhaps the world's most sought-after animals, but in all those legs, there is chemical gold. The humble arthropods have just opened new secrets-one which might actually be a cure for severe neurological disorders. With an avalanche of new research, millipedes, particularly from a subclass known as Colobognatha, are being highlighted by science for their powerful chemical defense chemicals.

This renewed interest stems from discoveries of diverse terpenoid alkaloids, a special kind of naturally occurring compound. These molecules are especially exciting because they interact with neuroreceptors in ways that could inspire future medicines. The focus of this discovery is Andrognathus corticarius, a small, forest-dwelling millipede whose name you’ll want to remember—because its chemistry could one day help relieve pain or treat neurological diseases.

Before 2020, relatively little research had been done on the chemical defense in Colobognatha millipedes, and only one order, Polyzoniida, had been said to produce terpenoid alkaloids. But now, an influx of research is showing that other orders, particularly Platydesmida, also produce these molecules—and with yet broader chemical diversity.

The new research, by Virginia Tech chemist Emily Mevers, focused on Andrognathus corticarius, an evolutionary cousin of other Platydesmida. It lives in leaf litter and fallen wood in a stand of trees known as Stadium Woods, on the Virginia Tech campus. It doesn't sound like an unusual location to go looking for pharmaceutical treasure, but these animals have proven to be bountiful sources of complex, new alkaloids.

Two new structural classes were disclosed from the defense secretions of the millipede: andrognathines and andrognathanols. The molecules are unprecedented in millipede chemistry. The scaffolds each bear a palette of fatty acids, generating an enormous collection of related molecules.

The most complex structure, the andrognathanol, possesses seven unbroken stereogenic centers—rare in naturally occurring compounds and difficult to assemble synthetically in the lab. These molecules are not something to be kept on display. Millipedes release them intentionally when physically threatened. In nature, that might be the presence of a predator—like an ant. In lab tests, the substances caused ants to act erratically, showing confusion and disorientation.

Millipedes are an old arthropod lineage. While ubiquitous in moist soil and leaf litter, their secretive nature so that much about their biology remains obscure. Relatively little is known about what they eat, how they behave, and their specific habitats. Their chemical ecology—what they produce, why, and how they came to do so—is even more black box.

Emily Mevers, who researches poorly explored chemical frontiers, worked alongside millipede specialist Paul Marek at Virginia Tech's department of entomology. They collected the millipedes from the forest floor and used powerful equipment, including mass spectrometry and nuclear magnetic resonance, to analyze the chemistry of the secretions.

Earlier, Mevers and Marek had worked with a different species of millipedes, Ischnocybe plicata, from the Pacific Northwest. The second species also provided alkaloids that acted against a neuroreceptor called Sigma-1. The receptor is important in the brain and has also been linked to the sensation of pain, neuroprotection, and some psychiatric disorders. The Ischnocybe alkaloids were shown to act selectively and effectively against Sigma-1—a favorable sign for drug-making.

Now that Mevers' team has found andrognathines and andrognathanols in A. corticarius, they've added another set of chemicals to their arsenal. Several of the new compounds even bind to the Sigma-1 receptor.

While the complete significance is still being researched, the replicability of this binding makes a stronger case that these alkaloids could serve as templates for novel medicines.

Natural compounds have been drug-discovery blueprints for centuries. Among the most powerful drugs, including antibiotics and cancer drugs, had their beginnings in bacteria, fungi, or plants. The same could one day be said of millipedes.

That won't happen easily, however. The chemical sophistication of compounds found in A. corticarius will be difficult to replicate in the laboratory. Those compounds are fairly complex, so they're going to take some time to synthesize in the laboratory," is Mevers' view.

To learn all about their medicinal potential, they need access first to bulk quantities. That will involve organic chemists stepping in and assembling the molecules in the highly controlled environment of a lab. After being synthesized, the compounds can then be studied in greater detail for their effect on human cells and eventually in animal models.

But even now, the promise is great. Sigma-1 is already a proven target in the discovery of new medicines, particularly for the control of chronic pain and neurodegenerative disease. Having natural molecules to work with it provides new ways for drug research.

This isn't a millipede tale per se—it's the tale of how underappreciated species can solve big problems. As scientists continue to discover the ecosystems that exist in plain sight, they're finding unexpected complexity and utility.

The research by Mevers adds a critical book to the growing body of chemical ecology literature. It illustrates that even the most inconspicuous of organisms can have useful compounds. It also indicates the worth of multidisciplinary partnerships.

Chemists, ecologists, and entomologists shared their talents and have been successful in shedding light on something which, not so many years ago, no one even knew existed.

The millipede may move slowly, but science is speeding along—and the hope is that what was once dismissed as "creepy crawly" could soon slither its way into medicine cabinets.

Research findings are available online in the Journal of the American Chemical Society.

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