Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products categorized by their unique threaded rotaxane structure. Genome mining studies from my group and others have revealed that these peptides are found in a wide variety of different prokaryotic organisms in environments as varied as the human gut and the deep sea. This proposal will leverage the latest generation of our genome mining software to catalog all known lasso peptides in sequenced genomes. We will continuously update this list and make it available to the natural products community. Leveraging our unique insights into lasso peptide activity, we will prioritize several peptides for further structural and functional studies. In particular, we plan to study lasso peptides predicted to have novel antimicrobial activities against pathogens. Finally, we will also leverage our genome mining work to carry out an in depth biochemical and structural study of lasso peptide biosynthesis.

Public Health Relevance

PROJECT RELEVANCE The proposed project focuses on the prediction and isolation of novel lasso peptides, a class of bioactive natural product. The project has a specific focus on identifying and producing lasso peptides with antimicrobial activity. This research will contribute to the arsenal of antibiotics available to treat infectious disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM107036-06
Application #
9739795
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Bond, Michelle Rueffer
Project Start
2014-08-01
Project End
2023-07-31
Budget Start
2019-09-01
Budget End
2020-07-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Princeton University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08543
Elashal, Hader E; Cohen, Ryan D; Elashal, Heidi E et al. (2018) Cyclic and Lasso Peptides: Sequence Determination, Topology Analysis, and Rotaxane Formation. Angew Chem Int Ed Engl 57:6150-6154
Zong, Chuhan; Cheung-Lee, Wai Ling; Elashal, Hader E et al. (2018) Albusnodin: an acetylated lasso peptide from Streptomyces albus. Chem Commun (Camb) 54:1339-1342
Zong, Chuhan; Wu, Michelle J; Qin, Jason Z et al. (2017) Lasso Peptide Benenodin-1 Is a Thermally Actuated [1]Rotaxane Switch. J Am Chem Soc 139:10403-10409
Chekan, Jonathan R; Koos, Joseph D; Zong, Chuhan et al. (2016) Structure of the Lasso Peptide Isopeptidase Identifies a Topology for Processing Threaded Substrates. J Am Chem Soc 138:16452-16458
Cheung, Wai Ling; Chen, Maria Y; Maksimov, Mikhail O et al. (2016) Lasso Peptide Biosynthetic Protein LarB1 Binds Both Leader and Core Peptide Regions of the Precursor Protein LarA. ACS Cent Sci 2:702-709
Allen, Caitlin D; Chen, Maria Y; Trick, Alexander Y et al. (2016) Thermal Unthreading of the Lasso Peptides Astexin-2 and Astexin-3. ACS Chem Biol 11:3043-3051
Zong, Chuhan; Maksimov, Mikhail O; Link, A James (2016) Construction of Lasso Peptide Fusion Proteins. ACS Chem Biol 11:61-8
Allen, Caitlin D; Link, A James (2016) Self-Assembly of Catenanes from Lasso Peptides. J Am Chem Soc 138:14214-14217
Piscotta, Frank J; Tharp, Jeffery M; Liu, Wenshe R et al. (2015) Expanding the chemical diversity of lasso peptide MccJ25 with genetically encoded noncanonical amino acids. Chem Commun (Camb) 51:409-12
Link, A James (2015) Biosynthesis: Leading the way to RiPPs. Nat Chem Biol 11:551-2

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