Oral Presentation 10th Australian Peptide Conference 2013

The Evolution of Anticancer Peptides from Self-Assembled Hydrogels (#60)

Joel Schneider 1
  1. NCI - Frederick, Frederick, MD, United States

We have designed a class of hydrogels from self-assembling beta-hairpin peptides that enable the direct three-dimensional encapsulation and subsequent localized delivery of small molecules, proteins or cells to tissue. Although cytocompatible towards mammalian cells1 , we found, through a serendipitous discovery, that some of these hydrogels kill a broad spectrum of drug-susceptible bacteria on contact.  Through de novo peptide design, we have been able to prepare next generation gels that have potent activity against drug-resistant strains of bacteria including MRSA and P. aeruginosa, a multi-drug resistant bacterium.2,3  . Based on our understanding of the mechanism of antibacterial action and the fact that bacteria and cancer cells share similar traits with respect to their cellular membranes, we have gone on to design a new class of non-gelling, soluble peptides that show anticancer activity against a broad array of cancer cells. 4  These peptides adopt an ensemble of random coil, bio-inactive conformations in solution.  However, when they encounter cancer cells, they bind to, and fold at, the cell’s surface, adopting a highly lytic conformation capable of killing the cell.  This surface-induced folding mechanism takes advantage of the aberrant lipid composition that characterizes many cancer cell types and allows these peptides to exert their action preferentially against cancerous as opposed to non-cancerous cells.

  1. Chomdao Sinthuvanich, Lisa A. Haines-Butterick, Katelyn J. Nagy and Joel P. Schneider, “Iterative Design of Peptide-based Hydrogels and the Effect of Network Electrostatics on Primary Chondrocyte Behavior”, Biomaterials, 2012, 33, 7478.
  2. Daphne A. Salick, Darrin J. Pochan and Joel P. Schneider, “Design of an Injectable -Hairpin Peptide Hydrogel that Kills Methicillin-Resistant Staphylococcus aureus” Advanced Materials, 2009, 21, 4120-4123.
  3. Ana Salome Veiga, Chomdao Sinthuvanich, Diana Gaspar, Henri G. Franquelim, Miguel Castanho, and Joel P. Schneider, “Arginine-rich Self-Assembling Peptides form Potent Antibacterial Gels”, BiomaterialsI, 2012, 33, 8907.
  4. Chomdao Sinthuvanich, Ana Salome Veiga, Kshitij Gupta, Diana Gaspar, Robert Blumenthal and Joel P. Schneider, “Anticancer -hairpin peptides: Membrane-induced folding triggers activity”, J. Am. Chem. Soc., 2012, 134, 6210.