For drug developers on the hunt for novel chemical matter, potential has emerged from an unlikely source: millipedes. Specifically, Andrognathus corticarius, a social, fungus-feeding arthropod tucked beneath rotting logs in North America, has just become the subject of a chemically intriguing natural product discovery.
Researchers from Virginia Tech and the National Cancer Institute have uncovered two previously unknown scaffolds from the A. corticarius millipede’s defensive secretions. These structures are considered structures so elaborate that they stretch the limits of synthetic feasibility – and offer new territory for chemical biology and receptor pharmacology.
Millipedes have long been recognized for their chemical defenses, but most studies have focused on simple benzoquinones and monoterpenes. The Colobognatha subterclass, comprising millipedes with unique social behaviors and parental care, stands out as the only known group to produce terpenoid alkaloids – a special group of naturally occurring chemicals that combine features of two big families of plant compounds: molecules built from isoprene units and nitrogen-containing compounds respectively. In terpenoid alkaloids, part of the molecule comes from the terpenoid pathway, and part comes from nitrogen-containing building blocks. The result is a hybrid structure that often has potent effects on living organisms. Historically, these compounds have been studied in only one order, the Polyzoniida millipede.
That has now changed with this study. After focusing on A. corticarius, the team uncovered a variety of terpenoid alkaloids with far more chemical diversity than previously described from millipedes. The two major compound families identified are:
Andrognathines: indolizidine-based 5,6-fused heterocycles with variable esterified fatty acid side chains.
Andrognathanols: an unprecedented 6,6,6,5-bridged polycyclic scaffold featuring seven contiguous stereogenic centers.
From a drug discovery perspective, the structural motifs reveal both synthetic challenges and molecular novelties that would be near-impossible to guess through in silico approaches. These compounds may engage with novel targets or function through unconventional mechanisms – an intriguing proposition for early-stage target discovery or phenotypic screening platforms, but the pharmacology of these compounds isn’t straightforward, and that’s where the opportunity lies.
Millipede ecology and pharmacology
The biological rationale for millipedes to produce such elaborate chemistry may offer hints about potential modes of action. Field assays showed that the alkaloids altered ant behavior, inducing extended immobility (a kind of “freezing” response) when ants encountered filter paper treated with millipede secretions. While not overtly toxic or repulsive, the behavioral modulation is consistent with subtle neuroactive properties.
This ecological evidence, combined with the structural complexity, positions andrognathines and andrognathanols as potential leads for neuropharmacological probe development, particularly in assays focused on locomotion, neuroplasticity, or even pain perception.
Only a small fraction (around ten percent) of Colobognatha species have been chemically characterized, suggesting the tip of the iceberg has barely been scratched. The authors note that even within a single species, chemical diversity can vary based on geography and individual size.
Of particular note to those in natural product sourcing or biosynthetic pathway discovery: each ozopore in A. corticarius houses 86 ± 68 ng of alkaloid material, and a mature individual can have over 100 ozopores. That adds up to surprisingly rich yields for an insect that fits in the palm of your hand.
Moreover, the presence of both compound classes in geographically distinct populations points to highly conserved biosynthetic machinery. This makes A. corticarius (and its relatives) promising models for bioprospecting or synthetic biology-based compound production.
Millipedes aren’t going to replace microbes or marine sponges in drug discovery workhorses, but they may quietly offer what so many synthetic libraries can’t: fresh, biosynthetically refined chemical matter that’s been tested by 400 million years of evolution. If you’re in early-stage discovery, now might be a good time to take a walk in the woods.
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