# Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $383,398

## Abstract

Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles
Natural peptide macrocycles are promising next-generation therapeutics, due to their abilities to bind to
challenging protein targets, such as protein interfaces and transcription factors. The goal of our lab is to use
insights and chemistries from natural product biosynthesis to facilitate the discovery and development of new
natural product-like peptide macrocycles. We will use a combined chemical and enzymatic approach for
synthesis of highly constrained peptide macrocycles similar to those used in nature. Over the next five years,
these efforts will be divided amongst three project areas. In the first project, we develop a chemoenzymatic
platform for the preparation of analogs of the thiopeptide natural products. We further exploit this platform to
examine new, diversity generating enzymes from complimentary ribosomal natural product pathways. In the
second project, we will investigate the multi-faceted biological activities of thiopeptides and develop potent and
selective inhibitors of the oncogenic transcription factor FoxM1. A major thrust of this research will be structure
elucidation of thiopeptides bound to FoxM1. In the final project, we combine enzymes from ribosomal peptide
natural product with mRNA display to allow laboratory scale directed evolution of new peptide macrocycle
inhibitors. This work is expected to yield new avenues and technologies for development of peptide macrocycle-
based therapeutics.

## Key facts

- **NIH application ID:** 10241273
- **Project number:** 5R35GM125005-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Albert A Bowers
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,398
- **Award type:** 5
- **Project period:** 2017-09-05 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241273

## Citation

> US National Institutes of Health, RePORTER application 10241273, Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles (5R35GM125005-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241273. Licensed CC0.

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