Mass cultivation of the dinoflagellate Alexandrium pacificum for gonyautoxin-1,4 production.

Bioactive venoms and toxins are emerging as a promising source of drug leads. Optimized through evolution, these compounds display remarkable selectivity and ligand affinity toward a range of relevant pharmacological targets. The successful development of new drugs from toxins is hampered in some areas by the chemical complexity of the active compounds, which limits the possibility of using chemical synthesis or recombinant strategies for drug lead generation. Marine paralytic shellfish toxins produced by marine microalgae is one such family of compounds. These compounds are highly potent blockers of voltage-gated ion channels, involved in regulating a range of physiological processes and thus versatile targets for drug development. To overcome the supply issue, the current paper describes the development of a scalable production method to generate gram amounts of gonyautoxin-1,4 by mass cultivation of the dinoflagellate Alexandrium pacificum in artificial seawater. By selecting a high-producing strain and running a series of growth optimization experiments, we have scaled up production from 100 mL to 1150 L, with cellular yields of toxin 30 times higher than in a natural bloom. This allows commercial production of gram amounts of these promising compounds, thereby enabling their use in a range of applications beyond the analytical scale.