Development of High Affinity Analogues of Brevenal: Novel Molecular Probes for Ne

DESCRIPTION (provided by applicant): The trans-syn class of marine polyether natural products produced by marine dinoflagellates are some of the most potent non-macromolecular biologicals known. Brevetoxins (PbTxs) and ciguatoxins (CTXs) are well known as the only ligands known to bind to site 5 on voltage-gated sodium channels (VGSCs) with high affinity. In 2004, we discovered brevenal, a third class of polyether ion channel modulator which counteracts the effects of site 5 toxic ligands. Unlike brevetoxins and ciguatoxins which are toxic in the nanomolar to picomolar concentration ranges, brevenal is non-toxic as far as we have investigated. More importantly, brevenal is an antagonist which negates, reduces, or prevents the effects of brevetoxin and ciguatoxin in every system examined. Receptor binding studies have demonstrated that brevenal does not directly compete for site 5 but non-competitively regulates PbTx activity. Biological testing showed brevenal to be antagonistic to the toxic effects of brevetoxins and ciguatoxins in vivo. In sheep inhalation models, brevenal blocks PbTx-induced bronchoconstriction and leads to increased tracheal mucous velocity. Implications for treatment of neurotoxic shellfish poisoning (NSP due to brevetoxin) and ciguatera fish poisoning (CFP due to ciguatoxin), or more broadly for the treatment of asthma, COPD or Cystic Fibrosis are supported through experimental results. In short, brevenal is a molecular class worthy of study. Key objectives of this proposal are to produce semi-synthetic brevenal derivatives that a) exhibit increased affinity (