Brevenal is being developed as a disease modifying agent for the treatment of mucociliary dysfunction in patients with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).
Brevenal was discovered serendipitously in Karenia brevis, a single cell oceanic algae.
When in bloom (Red Tide) K. brevis, which synthesizes numerous ladder frame polyether compounds, is responsible for fish, shellfish and marine mammal death. The toxic compounds isolated from K. brevis, the brevetoxins, are toxic due to their activating effect on voltage-sensitive sodium channels (VSSC, Nav) at pico-molar concentrations.
Multiple roles for these compounds were described in K. brevis. A recent report describes an increase in brevetoxin and brevenal production in K. brevis in response to sudden changes in salinity, which implicates a role in osmoregulation or osmotic sensing. Brevetoxins were shown to localize to the chloroplast of K. brevis where it binds to the light-harvesting complex II (LHCII) and thioredoxin. A culture of K. brevis producing low levels of toxin was shown to be deficient in non-photochemical quenching (NPQ) and produced reactive oxygen species at twice the rate of the toxic culture, implicating a role in NPQ for the brevetoxins.
Curiously, the organism synthesizes brevenal, which acts on VSSC in an opposite manner to the brevetoxins, inhibiting rather than activating sodium current.
In airway epithelium VSSC, Nav 1.7, localizes near the endothelia reticulum (ER) in the cytosol. Brevenal binds to a novel site on the receptor. Brevenal treatment results in intracellular calcium release, which activates the calcium activated chloride channels (CaCC) resulting in chloride secretion. In CF airway epithelial cells, it elicits the secretion of airway surface liquid (ASL) as well as in inhibition of inflammation mediated ASL absorption, thereby restoring airways homeostasis.
Brevenal reverses cystic fibrosis transmembrane conductance regulator inhibitor (CFTRinh-172) inhibition of pulmonary mucociliary clearance (MCC). Brevenal also inhibits the bronchoconstrictive effect of the inflammatory mediator, neutrophil elastase (NE), found in high concentrations in CF and COPD airways. Due to these effects, brevenal exerts a disease modifying effect for the treatment of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).
In in vitro and in vivo studies brevenal is additive to CFTR therapies. Brevenal can act as an adjuvant to CFTR therapies, as well as a sole therapy for patients with mutations not previously exploited by any other therapeutic agent. Improving normal lung function, clearing mucus and inhibiting inflammation will result in prevention of exacerbations, improved quality of life and possibly in prolongation of life.
Brevenal (C39H60O8; MW 656.4043) is manufactured from a proprietary strain of K. brevis in a biotechnology facility, under photosynthetic conditions. The compound is isolated from the cultured organism. This manufacturing process gives Silurian a unique competitive advantage; a well characterized small molecule, in a cell culture biotech environment.