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Cell penetrating guanidinoglycosides : design, synthesis, and uptake of multivalent guanidinylated Neomycin B

  • Author(s): Redgate, Christopher Patrick Houtby;
  • et al.

Drug discovery and cellular biology research have often been hindered by passage of large, charged molecules across the cellular membrane. Cell penetrating peptides (CPP) have a unique ability to cross this barrier and facilitate the uptake of other large cargo. Many CPP have a clustering of arginines and this observation brought about the discovery of the importance of guanidinium in facilitating their uptake. Guanidinoneomycin (GNeo) is from a class of membrane ferrying molecules called guanidinoglycosides, derivative of native antibiotic aminoglycosides. It has been shown to cargo large bioactive cargo (>300 kDa) across the membrane at nanomolar concentrations in a heparan sulfate proteoglycan (HSPG) dependant manner. Here, we describe the synthesis of flexible scaffolds that consist of one (monomeric) or two (dimeric) GNeo molecules. The dimeric GNeo molecule facilitates the uptake of a phycoerythrin-Cy5 conjugate (> 300 kDa) with more than two-fold efficiency than monomeric GNeo. Also, the dimer shows very high affinity for heparin, requiring a high NaCl concentration (2.6 M) for elution from a heparin column. The enhanced uptake of dimeric GNeo over monomeric GNeo could help further the understanding of GNeo/HSPG interactions. It is also shown that GNeo can facilitate the uptake of anionic cargo at very low concentrations, a unique property among guanidinium rich transporters

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