In the course of studying the mechanism by which these materials exert their antibacterial activity, we have discover that arginine content greatly influences the cytotoxic activity of the gels. Based on this discovery, we have designed a new class of peptide based gel, whose material surface can actively kill Gram positive and negative bacteria including multi drug resistant P. aeruginosa. No added antibacterial agents are necessary to realize activity. Gels prepared at 1.5 wt % or higher concentration, demonstrate high potency against bacteria, but are cytocompatible towards human erythrocytes as well as mammalian mesenchymal stem cells. Rheological studies indicate that the gel is moderately stiff and displays shear-thin recovery behavior, allowing its delivery via simple syringe. The hydrogel can be applied to clean surfaces to inhibit potential infections, and in addition, can be delivered to an infected site where bacterial cells are killed on contact. During the course of this study, we made a serendipitous discovery of a new class of soluble peptide that is effective at killing cancer cells. We used this discovery as the foundation to design an 18 residue anticancer peptide, SVS1, whose mechanism of action takes advantage of the aberrant lipid composition presented on the outer leaflet of cancer cell membranes. This composition makes the surface of these cells relatively electronegative relative to non-cancerous cells. SVS1 is designed to remain unfolded and inactive in aqueous solution but preferentially fold at the surface of cancer cells, adopting an amphiphilic beta hairpin structure capable of membrane disruption. Membrane induced folding is driven by electrostatic interaction between the peptide and the negatively charge membrane surface of cancer cells. SVS1 is active against a variety of cancer cell lines such as A549 (lung carcinoma), KB (epidermal carcinoma), MCF 7 (breast carcinoma) and MDA MB 436 (breast carcinoma). However, the cytotoxicity towards non-cancerous cells having typical membrane compositions, such as HUVEC and erythrocytes, is low. CD spectroscopy, appropriately designed peptide controls, cell based studies, liposome leakage assays and electron microscopy support the intended mechanism of action, which leads to preferential killing of cancerous cells. We plan to explore the utility of this peptide and design relatives in mouse models.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Ishikawa, Ken; Medina, Scott H; Schneider, Joel P et al. (2017) Glycan Alteration Imparts Cellular Resistance to a Membrane-Lytic Anticancer Peptide. Cell Chem Biol 24:149-158
Yamada, Yuji; Schneider, Joel P (2016) Fragmentation of Injectable Bioadhesive Hydrogels Affords Chemotherapeutic Macromolecules. Biomacromolecules 17:2634-41
Medina, Scott H; Miller, Stephen E; Keim, Allison I et al. (2016) An Intrinsically Disordered Peptide Facilitates Non-Endosomal Cell Entry. Angew Chem Int Ed Engl 55:3369-72
Medina, Scott H; Schneider, Joel P (2015) Cancer cell surface induced peptide folding allows intracellular translocation of drug. J Control Release 209:317-26
Nagy-Smith, Katelyn; Moore, Eric; Schneider, Joel et al. (2015) Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network. Proc Natl Acad Sci U S A 112:9816-21
Urano, Emiko; Ablan, Sherimay D; Mandt, Rebecca et al. (2015) Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors. Antimicrob Agents Chemother 60:190-7
Sonmez, Cem; Nagy, Katelyn J; Schneider, Joel P (2015) Design of self-assembling peptide hydrogelators amenable to bacterial expression. Biomaterials 37:62-72
Giano, Michael C; Ibrahim, Zuhaib; Medina, Scott H et al. (2014) Injectable bioadhesive hydrogels with innate antibacterial properties. Nat Commun 5:4095
Veiga, Ana Salomé; Schneider, Joel P (2013) Antimicrobial hydrogels for the treatment of infection. Biopolymers 100:637-44
Sinthuvanich, Chomdao; Veiga, Ana Salomé; Gupta, Kshitij et al. (2012) Anticancer ?-hairpin peptides: membrane-induced folding triggers activity. J Am Chem Soc 134:6210-7

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