Leveraging Mexican Millipede Secretions as Neuromodulators - Project summary/abstract New treatments of neurological disorders are desperately needed, especially in regions with significant and disproportionately unmet needs, such as in Mexico. Although Mexico's incidence of chronic pain is on par with that in the US, their utilization of current treatments only amounts to 0.56% of the level seen in the US. Development of natural products from organism's native to Mexico for the treatment of pain has the potential of fewer perceived risks and may overcome challenges of current therapeutics. The goal of this project is to establish millipedes as a source of natural products that can be leveraged for the treatment of pain. The success that natural products have had clinically is due to their ancient evolutionary history; their structures and functions evolved over millions of years of selection to carry out an essential role for the organism. For example, many of the antibiotics applied today are produced by terrestrial microorganisms that use them to vanquish competitors. Millipede natural products are no different. Different millipedes have evolved the ability to produce unique defensive metabolites, including hydrogen cyanide, oxidized aromatics, and terpenoid alkaloids. These metabolites change in structural complexity through evolutionary time. Their structural diversity is correlated with phylogeny, and the conservation of biosynthetic pathways along with the evolution of gland anatomy to store these metabolites are strong indicators of their important ecological role. The terpenoid alkaloids, nitrogen containing heterocycles, are the least studied but simultaneously the most interesting from a biological perspective. Less than 10% of the alkaloid producing millipedes have been investigated and each one has led to a new chemistry with unprecedented carbon backbones. Most notably, we recently showed that two different subsets of these molecules bind potently and specifically to two different receptors (sigma-1, and sigma- 2) with each receptor having been implicated for the treatment of neurological disorders, including chronic pain. Our research team proposes to study millipedes native to Mexico to investigate the relationship between molecular phylogeny and chemical diversity to uncover novel natural products with important biological activity. Our team's expertise in millipede ecology specific to Mexico, natural products chemistry, and biochemistry, will lead to the discovery of millipedes producing new bioactive alkaloids. Novel natural products will be isolated, structurally characterized, and biochemically evaluated to fully understand their therapeutic potential. Collectively, our proposed research program will broadly impact the field by showing that millipedes native to Mexico are a repository of many new biologically relevant natural products. Studying these small molecules will lead to the discovery of novel sigma-1 and sigma-2 ligands that have the potential to populate the drug pipeline, specifically for the treatment of chronic pain, without the perceived risks of current treatments.
