We previously designed a class of antibacterial hydrogels from self-assembling beta-hairpin peptides that kill a broad spectrum of drug–resistant bacteria on contact.  Based on an understanding of the gels’ lytic mechanism of action and the fact that bacteria and cancer cells share similar traits with respect to their cell surfaces, we have gone on to design a new class of non-gelling, soluble peptides that show cytotoxic activity against a broad range of cancer cells. These anticancer peptides (ACPs) 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 cells. In general, most ACPs disrupt tumor cell membranes through rapid and non-stereospecific mechanisms, encouraging the perception that cellular resistance towards their action is unlikely to occur. Interestingly, although resistance towards small molecular chemotherapeutics has been well studied, the potential of tumor cells to avoid destruction by membrane-lytic compounds remains largely unexplored. We demonstrate that eukaryotic cells can, indeed, develop resistance to oncolytic peptides. Utilizing fission yeast as a model organism, we show that ACP resistance is largely controlled through the loss of cell-surface anionic saccharides. We then discovered a similar mechanism in mammalian cancer cells where removal of negatively-charged sialic acid residues directly transforms a peptide sensitive cell line into a resistant phenotype. These results demonstrate that changes in cell-surface glycosylation play a major role in tumor cell resistance towards oncolytic peptides.

Tit for tat: Design evolution of anticancer peptides from self-assembled hydrogels and how cancer cells gain resistance to their action

253rd National Meeting (2017)

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