Small Molecule Receptors for Membrane Lipids Project Summary Cell membranes consist of a variety of lipids. It is clear that they do not simply serve as a physical barrier of a cell. Instead the composition and distribution of membrane lipids have significant ramifications for physiology and disease. For example, bacterial and mammalian cells display dramatically different compositions in their plasma membranes, with bacterial membrane harboring a large percentage of the negatively charged phosphatidylglycerol (PG). Another well known example is phosphatidylserine (PS), which in healthy mammalian cells is exclusively confined to the inner leaflet of the plasma membrane. Externalization of PS to the cell surface is a hallmark event of apoptosis, a primary mechanism of cell death. While we begin to appreciate the significance of lipids, much remains to be uncovered on the intricate details of their function in a variety of biological processes. Toward this end, small molecules that recognize a specific lipid are highly desirable for profiling the spatiotemporal distribution of lipids. We hypothesize that small cyclic peptides could serve as an effective and versatile scaffold for designing low molecular weight receptors for membrane lipids. Our preliminary studies demonstrated the feasibility of this approach: cyclic peptides mimicking the natural protein lactadherin (cLac) display protein-like specificity for PS and effectively label apoptotic cells.
Aim 1 of this submission seeks to further develop the cLac design as PS receptors. We will explore the potential of pre- organization, polyvalency and covalent chemistry to improve the binding affinity and specificity of cLac towards PS-presenting membranes. Using the cLac peptide as a blueprint, we will design solid phase supported libraries of cyclic peptides. Screening of the peptide libraries will enable discovery of small molecule receptors for a variety of lipids.
In aim 2 of this proposal, we will expand the cyclic peptide design to develop ligands for the bacterial lipid PG. Specifically, we will use the cyclic scaffold to display chemical functionalities that bind PG head groups through covalent chemistry. The capability of targeting PG will enable novel strategies for the design of membrane-lytic antibiotics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
4R01GM102735-05
Application #
9104164
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
Hosseini, Azade S; Wang, Wenjian; Haeffner, Fredrik et al. (2017) Metal-Assisted Folding of Prolinomycin Allows Facile Design of Functional Peptides. Chembiochem 18:479-482
Cambray, Samantha; Bandyopadhyay, Anupam; Gao, Jianmin (2017) Fluorogenic diazaborine formation of semicarbazide with designed coumarin derivatives. Chem Commun (Camb) 53:12532-12535
Bandyopadhyay, Anupam; Cambray, Samantha; Gao, Jianmin (2017) Fast Diazaborine Formation of Semicarbazide Enables Facile Labeling of Bacterial Pathogens. J Am Chem Soc 139:871-878
Gao, Jianmin (2017) Cation-? Lights Up ""Halo"". Biochemistry 56:5221-5222
Bandyopadhyay, Anupam; Cambray, Samantha; Gao, Jianmin (2016) Fast and selective labeling of N-terminal cysteines at neutral pH via thiazolidino boronate formation. Chem Sci 7:4589-4593
Lee, Yan-Jiun; Schmidt, M J; Tharp, Jeffery M et al. (2016) Genetically encoded fluorophenylalanines enable insights into the recognition of lysine trimethylation by an epigenetic reader. Chem Commun (Camb) 52:12606-12609
Bandyopadhyay, Anupam; Gao, Jianmin (2016) Targeting biomolecules with reversible covalent chemistry. Curr Opin Chem Biol 34:110-116
Bandyopadhyay, Anupam; Gao, Jianmin (2016) Iminoboronate-Based Peptide Cyclization That Responds to pH, Oxidation, and Small Molecule Modulators. J Am Chem Soc 138:2098-101
Bandyopadhyay, Anupam; McCarthy, Kelly A; Kelly, Michael A et al. (2015) Targeting bacteria via iminoboronate chemistry of amine-presenting lipids. Nat Commun 6:6561
Bandyopadhyay, Anupam; Gao, Jianmin (2015) Iminoboronate Formation Leads to Fast and Reversible Conjugation Chemistry of ?-Nucleophiles at Neutral pH. Chemistry 21:14748-52

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