Discovering small molecule ligands with a high affinity for voltage-gated sodium channels and specificity for disease relevant isoforms is challenging. Common synthetic strategies require prefunctionalization to introduce heteroatoms and larger functional groups, rendering the molecules difficult to handle, purify, and subject to further diversification. Nature approaches such synthetic bottlenecks by constructing simple cores and decorating scaffolds later on in biosynthesis. Chemists take inspiration from Nature?s techniques in designing late-stage C?H functionalization routes, but the ability of enzymes to generate molecular complexity is unmatched by state-of-the-art synthetic methods. Thus, biocatalysis represents a unique approach to tackling the synthetic challenges associated with drug design. Paralytic shellfish toxins (PSTs) are an untapped source of antiepileptic drug targets. Over 50 naturally derived PSTs have been identified, and the select few that have been assessed for binding to voltage-gated sodium channels (VGSCs) have demonstrated the ability to block VGSCs. This molecular response corresponds to physical responses desired in antiepileptic drug targets. The study of PSTs as antiepileptic drug targets has been hindered by challenging synthetic routes and the inability to isolate sufficient quantities of most of the >50 analogs. Gene clusters associated with paralytic shellfish toxin biosynthesis have been identified, enabling opportunities to leverage enzymes capable of chemistry inaccessible to even the most skilled chemist. This proposal describes strategies to elucidate the paralytic shellfish toxin biosynthetic pathway, evaluate enzyme substrate scopes, and isolate novel compounds from biocatalytic reactions for analysis with VGSCs using electrophysiological techniques. In summary, this work aims to diversify the PST scaffold using PST biosynthetic enzymes from cyanobacteria, enabling chemical transformations on complex, heteroatom-rich molecules that are otherwise intractable. The methods established in this proposal will accelerate the discovery of new antiepileptic drugs by developing new chemical reactions using biocatalysts from the biosynthetic pathway of known VGSC blocking compounds.

Public Health Relevance

The proposed research seeks to impact human heath through the discovery of new small molecules that can be applied to the study of voltage-gated sodium ion channels and the treatment of channelopathies such as epilepsy. Enzymes involved in the biosynthesis of paralytic shellfish toxins will be employed as biocatalysts to generate and diversify small molecules implicated in blocking voltage-gated sodium channels which are exceedingly challenging to synthesize. Ultimately, this work will accelerate the development of new antiepileptic drugs based on a valuable bioactive scaffold.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Whittemore, Vicky R
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University of Michigan Ann Arbor
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Ann Arbor
United States
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