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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM107036-01A1
Application #
8751459
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Gerratana, Barbara
Project Start
2014-08-01
Project End
2019-03-31
Budget Start
2014-08-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$280,519
Indirect Cost
$88,019
Name
Princeton University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544