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Chem Sci. 2016 Aug 1;7(8):5059-5068. doi: 10.1039/C6SC00488A. Epub 2016 Apr 25.

Polymyxins Facilitate Entry into Mammalian Cells.

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Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92093-0358, USA.
Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093-0687, USA.


Polymyxin B is an antibiotic used against multi-resistant gram negative infections, despite observed nephrotoxicity. Here we report the synthesis of functionalized derivatives of polymyxin B and its per-guanidinylated derivative in order to further explore the structural requirements necessary to facilitate uptake of the antibiotic into mammalian cells. We also investigate the possibility of using these novel scaffolds as molecular transporters. At nanomolar concentrations, both are capable of delivering large cargo (>300 kDa) into living cells. Their uptake depends exclusively on cell surface heparan sulfate. Mechanistic studies indicate these novel transporters are internalized through caveolae-mediated pathways and confocal microscopy show colocalization with lysosomes. The polymyxin-based transporters demonstrate cytosolic delivery through the delivery of a ribosome-inactivating toxin. Furthermore, the natural polymyxin scaffold can be incorporated into liposomes and enhance their intracellular uptake. In addition to demonstrating the ability of the polymyxin scaffold to facilitate internalization into mammalian cells, these observations suggest the potential use of polymyxin and guanidinopolymyxin for intracellular delivery.

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