# Synthetic Biology Approaches to New Fluorinated Pharmaceuticals

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $80,000

## Abstract

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Project Summaries
 PROJECT 1: Synthetic biology approaches to new fluorinated pharmaceuticals (1R01GM123181-
01): Fluorinated pharmaceuticals represent a rapidly expanding class of small molecule drugs that have
become important in the treatment of diverse human health conditions ranging from cancer to high
cholesterol. The focus of this project is to develop synthetic biology approaches to engineering enzymatic
and living systems for the production of complex fluorinated compounds with bioactivity, with the long-
term goal of developing new approaches to fluorinated drug discovery. Specific aims of this proposal
include: (i) elucidating the molecular mechanism of naturally-occurring fluorine selectivity in enzymes
from Streptomyces cattleya, one of the few known native organofluorine-producing organisms, in order to
build a knowledgebase for engineering fluorine-selective enzymes, (ii) studying the mechanism of
fluorinated extender unit usage in polyketide synthases, which produce a large family of medicinally-
important natural products, and (iii) developing in vitro and in vivo methods for production of fluorinated
natural products in the polyketide family.
 PROJECT 2: Discovery and application of new halogenases (R01GM134271): The rapid and
modular generation of molecular diversity is key to the search for new chemical functions. One particularly
useful functional group is the halogen (X = Cl, Br, I), which enables many selective and effective
downstream strategies for creating structural complexity. In this regard, halogenase enzymes have provided
an important and complementary approach to synthetic catalysts for regio- and stereoselective introduction
of a halogen substituent on a complex scaffold. While many families of halogenases exist, the radical
halogenases provide the greatest potential for reaction diversity, as they are competent to replace
unactivated C-H bonds with a halogen unlike those that operate by electrophilic or nucleophilic
mechanisms. However, the substrate scope of these enzymes has been limited to date to either protein-
bound substrates or large late-stage natural product intermediates. Our group has discovered a new clade
of radical halogenases capable of reacting with small molecule substrates. We now seek to take advantage
of this discovery to develop new tools for in vitro and in vivo synthesis. Specific aims of this proposal
include: (i) elucidating the structure and mechanism of these new radical halogenases, which will provide
important insight into their engineering, (ii) investigating and engineering selectivity in halogenases.

## Key facts

- **NIH application ID:** 10135371
- **Project number:** 3R01GM123181-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** MICHELLE C CHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $80,000
- **Award type:** 3
- **Project period:** 2017-04-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135371

## Citation

> US National Institutes of Health, RePORTER application 10135371, Synthetic Biology Approaches to New Fluorinated Pharmaceuticals (3R01GM123181-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10135371. Licensed CC0.

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