# Prenylated-Flavin Enzymes as a new Platform for Drug Synthesis and Discovery > **NIH NIH F32** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $64,926 ## Abstract Project Summary/Abstract The discovery and synthesis of small molecules that possess favorable biological properties have markedly enhanced the quality of human life. Current methods for the synthesis of these drug compounds, however, rely heavily on environmentally-harsh solvents and reactions that frequently offer only limited selectivity for the desired outcome. In recent years, enzymes have been increasingly used in conjunction with synthetic reactions to yield products with unparalleled selectivity and without the necessity of harmful solvents. Engineering new enzyme platforms for novel reactivity will expand the collection of biocatalysts that are beneficial to the drug development process, and is thus a goal worth pursuing. Directed evolution has proved to be an unrivaled technique for the development of enzymes that exhibit exquisite catalytic capabilities toward an array of desired reactions. From P450s to TrpB enzymes, many natural scaffolds have been evolved to catalyze reactions that are both known and new to biology, effectively expanding our synthetic toolbox. The research proposed herein aims to engineer prenylated-flavin (prFMN) enzymes by directed evolution to generate biocatalysts that can pave the way to more cost-effective avenues to drug compounds used for the treatment of human diseases. To this end, previously-characterized prFMN enzymes will be applied to a non- native C–C coupling reaction that will ultimately produce chiral allylic and aromatic alcohols. This chemical moiety is found in numerous drug scaffolds; however, the current synthetic procedures often grant insufficient control over the product stereochemistry. A second objective is to apply prFMN enzymes to aromatic acylation reactions, a similar C–C coupling reaction described above that will result in diverse and complex molecular scaffolds. Crafting new synthetic avenues to complex and diversifiable ring structures is important to the drug discovery process by the philosophy of diversity-oriented synthesis. A third objective is to redirect the native prFMN reactivity toward the aromatic carboxylation of large, ring-bearing compounds. Late-stage carboxylation of complex molecular scaffolds can provide another branchpoint to produce libraries of complex and diverse molecules for bioactivity screening and drug discovery. Directed evolution will be applied throughout each aim to engineer enzyme variants capable of catalyzing the chemical transformations with a high degree of specificity. The biocatalysts developed herein may also serve as a platform for future engineering endeavors involving the prFMN cofactor. ## Key facts - **NIH application ID:** 9982049 - **Project number:** 5F32GM131620-02 - **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY - **Principal Investigator:** Noah Paul Dunham - **Activity code:** F32 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $64,926 - **Award type:** 5 - **Project period:** 2019-08-01 → 2021-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9982049 ## Citation > US National Institutes of Health, RePORTER application 9982049, Prenylated-Flavin Enzymes as a new Platform for Drug Synthesis and Discovery (5F32GM131620-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9982049. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*