# Biocatalytic generation of bioactive biaryl natural products

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $37,156

## Abstract

PROPOSAL SUMMARY
Plants that produce biaryl natural products have a long history of medicinal use in naturopathic remedies due to
the potent biological activities manifested by the biaryl architecture of these molecules. Over the last several
decades, the biaryl scaffold has been widely acknowledged as a privileged structure in drug discovery; however,
the full exploration of the medicinal properties and therapeutic development of natural products harboring biaryl
scaffolds is hindered by the inability to isolate significant quantities of these compounds through natural sources
or chemical synthesis. The potent biological activities of these natural products are contingent upon the axial
chirality of the biaryl bond, yet forming a biaryl bond with this selectivity and precision remains a fundamental
challenge in organic synthesis which has limited our access to these natural products. In contrast, Nature has
evolved enzymes capable of forming these critical biaryl bonds with excellent selectivity. I aim to engineer these
enzymes into robust biocatalysts capable of catalyzing the formation of axially chiral biaryl bonds with catalyst-
controlled site-selectivity unmatched with conventional chemical methods. Through the directed evolution of
these enzymes, I will synthesize biaryl natural products that have demonstrated potent and diverse biological
activity, yet are currently understudied primarily due to their current inaccessibility. The two classes of biaryl
natural products that I aim to access are biflavonoids and naphthylisoquinoline alkaloids. Both of these classes
of natural products harbor the privileged axially chiral biaryl architecture and have demonstrated largely untapped
therapeutic potentials. Most significantly, many biflavonoids exhibit anti-hepatitis B virus and anticancer activity
and many naphthylisoquinoline alkaloids exhibit antimalarial and anti-HIV activity. Developing this biocatalytic
platform will provide access to a library of these pharmacologically promising natural products and their
derivatives, thereby accelerating their therapeutic development for applications including hepatitis B, cancer,
malaria, and HIV/AIDS.

## Key facts

- **NIH application ID:** 9989956
- **Project number:** 1F31AT010973-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lara Emily Zetzsche
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,156
- **Award type:** 1
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989956

## Citation

> US National Institutes of Health, RePORTER application 9989956, Biocatalytic generation of bioactive biaryl natural products (1F31AT010973-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9989956. Licensed CC0.

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