# Discovery, Biosynthesis and Engineering of Side-Chain-Macrocyclic Plant Peptides

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $339,800

## Abstract

PROJECT SUMMARY
Plants have been an important source of medicinal natural products, as ~25% of FDA-approved drugs are
inspired by plant chemicals. However, discovery and development of new pharmaceuticals based on plant
natural products is challenging due to three main bottlenecks: (1) rediscovery of known compounds from complex
plant extracts during bioactivity-guided discovery approaches, (2) difficult scaled production of chemically
complex lead structures by organic synthesis or source plant extraction, and (3) limited diversification of lead
structures due to molecular complexity. Recent advances in plant omics-technologies and plant synthetic biology
offer solutions to these general bottlenecks of natural product drug discovery by a gene-guided discovery
approach. Herein, prioritization of new plant metabolites can be enabled by mass spectrometry (MS)-based
metabolomics of plant extracts and prediction of biosynthetic genes from plant genomes. Heterologous
expression of biosynthetic genes allows source-independent production of target plant natural products in
microbial and eukaryotic host organisms. Genetic modification of biosynthetic pathways enables the formation
of target natural product analogs. Cyclic plant peptides are a class of plant natural products with potential
applications in antiviral and anticancer therapy due to oral bioavailability, stability and diversifiability. Our lab
recently characterized a new plant-specific peptide cyclase called the BURP domain, which is an autocatalytic
copper-dependent enzyme family involved in the biosynthesis of ribsomally encoded and posttranslationally
modified peptides (RiPPs) with side-chain-macrocyclizations via tyrosines and tryptophans. Our objective is to
overcome the aforementioned bottlenecks of plant-based drug discovery by developing a workflow for the
systematic discovery of cyclic peptides from plants, characterizing BURP domain peptide cyclases for scaled in
vivo or in vitro production of cyclic plant peptides and establishing a biocatalytic platform for the diversification of
cyclic plant peptides via BURP domain cyclases for therapeutic evaluation. Herein, systematic identification of
new side-chain-macrocyclic RiPP classes will be accomplished by connecting tandem MS spectra of candidate
peptide analytes to BURP domain genes in plant genomes and transcriptomes. We will investigate the structure
and function of known autocatalytic classes of BURP domain peptide cyclases, characterize BURP domain
peptide cyclases, which act on separate precursor peptide substrates and identify enzymes involved in N- and
C-terminal protection of BURP-domain-derived RiPPs. Finally, libraries of antiviral cyclopeptide alkaloids from
Chinese date tree (Ziziphus jujuba) and anticancer celogentin peptides from Celosia argentea will be generated
by design and optimization of biocatalytic routes and evaluated in in vivo cell-based assays. As plant genomic
resources are rapidly growing, the proposed re...

## Key facts

- **NIH application ID:** 10497233
- **Project number:** 1R35GM146934-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Roland David Kersten
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,800
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10497233

## Citation

> US National Institutes of Health, RePORTER application 10497233, Discovery, Biosynthesis and Engineering of Side-Chain-Macrocyclic Plant Peptides (1R35GM146934-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10497233. Licensed CC0.

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