Lasso peptides are ribosomally-synthesized, posttranslationally-modified natural products that adopt a remarkable slipknot-like structure. All currently lasso peptides possess a therapeutically relevant function, ranging from antimicrobial activity to inhibition of HIV. The knotted structure of lasso peptides endows the molecules with tremendous resistance to thermal and chemical denaturation and resistance to most proteases. Because of this stability, lasso peptides are a compelling scaffold for peptidic drug discovery efforts. The current proposal is focused on 1) heterologous expression and structural characterization of novel lasso peptides discovered in a genome mining study and 2) studies on a novel enzyme, lasso peptide isopeptidase, and its connection to a potential siderophore function in lasso peptides.

Public Health Relevance

The proposed project involves the discovery, characterization, and determination of therapeutic utility of new lasso peptide natural products. Lasso peptides highly stable and resistant to proteases, and thus are expected to have vastly improved pharmacological properties relative to conventional peptides. All known examples of lasso peptides have a therapeutically relevant function. Moreover, the lasso peptide scaffold is readily engineered using recombinant DNA technology and thus holds promise as a starting point for peptide drug discovery.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Gerratana, Barbara
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Princeton University
Engineering (All Types)
Schools of Engineering
United States
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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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