# Biocatalytic approaches to antiepileptic drug targets

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $11,980

## Abstract

Proposal Summary
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.

## Key facts

- **NIH application ID:** 9922670
- **Project number:** 5F31NS111906-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** April Lukowski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $11,980
- **Award type:** 5
- **Project period:** 2019-05-01 → 2020-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922670

## Citation

> US National Institutes of Health, RePORTER application 9922670, Biocatalytic approaches to antiepileptic drug targets (5F31NS111906-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9922670. Licensed CC0.

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