Cyclic peptides have been explored as ligands against a wide variety of biological targets. They are relatively easy to synthesize, and, at the same time, exhibit a degree of complexity unrivaled by most other classes of small molecules. However, cyclic peptides often suffer from poor cell permeability, a characteristic common to peptides in general. Indeed, a key bottleneck in drug development lies in the inability to predict and control factors that govern cell permeability in small molecules. The global objective of our research program is to create a new generation of biologically active, cell permeable cyclic peptides as probes and lead antibiotic and antifungal compounds. In this proposal, we seek to broaden our understanding of membrane permeability in this important class of compounds by testing hypotheses regarding the influence on backbone conformation, ring size, and side chain functionality, on the passive membrane diffusion of cyclic peptides. Taking a lesson from natural products, cell permeability in cyclic peptides is often determined by key modification - namely, N-methylation of one or more peptide amides - that help to transport the polar backbone across the hydrophobic lipid bilayer. Here we apply a powerful new approach to regioselective N-methylation to generate libraries of cyclic peptides that exhibit improved membrane permeability over their non-methylated counterparts. In addition, we will develop a strategy for the sulfenylation of cyclic and linear peptides, generating bioreversible prodrugs with greatly improved membrane permeability relative to their unmodified parent compounds. Finally, we have put in place a panel of high-throughput phenotypic screens in yeast, bacteria (V. cholera), and mammalian cells for compounds that modulate a wide variety of biological processes. Using the methods developed in the first three aims, we will generate libraries of natural product-inspired, membrane permeable cyclic peptides for input into these screens, with the end result being a collection of potent bioactive compounds poised for further development.

Public Health Relevance

The overall objective of our research program is to understand the structural basis of membrane permeability in small molecules. We propose to use cyclic peptides as molecular scaffolds to study the conformational basis of permeability, and apply what we learn to create a new generation of biochemical probes. We combine computational approaches with synthetic organic chemistry and high-throughput screening to develop a new class of bioactive cyclic peptides inspired by natural products. We expect that new antibiotics and antifungal agents will emerge from this project.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084530-09
Application #
8291316
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2003-09-29
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$284,955
Indirect Cost
$84,034
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
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Turner, Rushia A; Hauksson, Niels E; Gipe, Jordan H et al. (2013) Selective, on-resin N-methylation of peptide N-trifluoroacetamides. Org Lett 15:5012-5
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White, Tina R; Renzelman, Chad M; Rand, Arthur C et al. (2011) On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat Chem Biol 7:810-7