Cell penetrating agents based on a polyproline helix scaffold.
Cell penetrating agents were designed and synthesized that introduce cationic and hydrophobic moieties along the backbone of a polyproline helix (PPII) in an amphiphilic manner. The CD profile has the features that are expected for a PPII helix, demonstrating that the addition of these groups had little effect on the backbone structure. Dramatic increases in uptake were found with MCF-7 cells when up to six guanidinium groups were positioned on the polyproline helix, whereas only modest increases in cellular uptake were observed with the amine-containing polyproline compounds as compared to their flexible counterparts. Amphiphilicity played a key role in the enhanced cell translocation, as scrambled versions of the designed agents, with hydrophobic and cationic groups on all faces of the helix, were only as effective as their flexible peptide counterparts. Interestingly, the most potent agent, P11LRR, demonstrated almost an order of magnitude more efficient cellular uptake as compared to that of the well-studied Tat peptide, with minimal cytotoxicity.
Fillon
Yannick A
YA
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA.
Anderson
Jason P
JP
Chmielewski
Jean
J
D001943:Breast Neoplasms / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary
D004337:Drug Carriers; D010455:Peptides; C011083:polyproline