Irelands’ hidden pharmacy: Marine biodiscovery applied to deep-sea sponges and corals

Afoullouss, Sam
Natural products have provided over 60% of our medicines to date, but their search has focused on easy to access habitats, leaving the marine realm underexplored. The deep-sea, which is the world’s largest biome and contains some of the most biodiverse and inaccessible ecosystems, could represent an untapped source of natural products, especially since harsh environmental gradients and competition for resources in deep-sea habitats can lead to evolutionary adaptations with the potential to yield novel internal chemistry. A series of three expeditions to Ireland’s continental slope and associated submarine canyon systems, collected corals and sponges from rich habitats. As part of a wider project whose aim was to isolate novel bioactive deep-sea metabolites with pharmaceutical potential, herein focus was applied to two species. Characella pachastrelloides was selected because of the interesting chemical profile of an initial extract. Paragorgia arborea was selected for its bioactivity in a screening programme. Four novel glycolipopeptides which contain a rare sugar moiety and rare D-amino acids were extracted and elucidated from the deep-sea sponge Characella pachastrelloides collected in Whittard Canyon at 800 m depth. These four compounds represent two pairs of stereo enantiomers which differ in the length of the fatty acid chain. Enantiomers Characellide A and B showed potent anti-inflammatory activity in a bioassay measuring ROS production. Subsequent synthesis of Characellide A by international colleagues demonstrated that further analysis of the absolute configuration of the natural product is required. It became apparent that optimisation of classical and feature-based data acquisition parameters was required to effectively apply molecular networking to fractions of the Characella pachastrelloides extract. A fractional factorial analysis applied to three extracts (an alga, a sea squirt and a zoanthid) that varied widely in their chemodiversity showed that four factors have the greatest effect on molecular network topology: concentration, liquid chromatography separation, the number of precursors per cycle, and collision energy. The relative importance of factors varied between featured-based and classical molecular networking and depends on the planned application of the network itself. Using the optimised data acquisition parameters for molecular networking the full chemodiversity of Characella pachastrelloides was analysed. This led to the discovery and elucidation of two additional characellides, light sensitive poecillastrins (cytotoxic polyketides), and a novel methylated histidine (6-methyl hercynine) whose imidazole ring has a unique methylation pattern not previously seen in nature whereby the methylation occurs on a C. In addition, cyanocobalamine was identified revealing its occurrence in nature for the first time. Bioactivity screening led to prioritisation of the bubble gum coral Paragorgia arborea for natural product isolation. New bicyclic diterpenoids were elucidated. These included two miolenols with a rare cyclobutanol ring and one new and five known xeniolides. Miolenol showed interesting conformational flexibility as evidenced by temperature-variable NMR and NOESY correlations. All diterpenoids showed mild anti-plasmodial activity and the known compound 9-deoxyxenolide showed strong activity against a drug-resistant strain of malaria. This discovery of new and novel compounds illustrates the untapped chemistry of the deep sea. The pharmaceutical potential shown by these metabolites further highlights the importance of this biome in future drug discovery efforts.
Science Foundation Ireland
NUI Galway
Publisher DOI
Attribution-NonCommercial-NoDerivs 3.0 Ireland
CC0 1.0 Universal