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.

Public Health Relevance

Natural product biosynthetic pathways make complex, synthetically challenging molecules that inhibit high value therapeutic targets. Here we are using a newly discovered classes of enzymes from natural product pathways to make new therapeutic scaffolds and to probe and improve the anticancer activity of thiopeptide natural products. These studies will provide new chemoenzymatic methods for preparation of complex, natural product-like molecules and new insights into means of inhibiting cancer by targeting oncogenic transcription factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM125005-01
Application #
9382629
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fabian, Miles
Project Start
2017-09-05
Project End
2022-08-31
Budget Start
2017-09-05
Budget End
2018-08-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599