MEDI 229 |
| A series of experiments will be presented that provide a mechanistic hypothesis for how short oligomers of arginine can migrate across the plasma membrane of a cell. The water soluble, positively charged guanidinium headgroups of the transporter form bidentate hydrogen bonds with H-bond acceptor functionality on the cell surface, with ion exchange of its counterions. The resultant ion pair complexes partition into the lipid bilayer and migrate across at a rate related to the membrane potential. The complex dissociates on the inner leaf of the membrane and the transporter enters the cytosol. This mechanism is consistent with the apparent lack of stereospecificity in the process, because the key feature is the formation of the bidentate hydrogen bonds with the guanidine head groups, and not the stereochemistry of the backbone. Similar logic explains why there is neither a structural requirement for a unique spacing of the guanidines extending from the backbone, nor along the backbone and even can rationalize why dendrimers and oligosaccharides decorated with sufficient number of guanidines are transported effectively. The requirement for a minimum number of guanidines required for transport is explained because peptides with greater guanidine content will form more hydrogen bonds and bind to the surface with greater affinity, thus increasing the local concentration. This hypothesis does not preclude competing uptake by other mechanisms including endocytosis, which is likely to dominate with large cargos. |
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Drug Delivery
1:30 PM-4:50 PM, Tuesday, August 21, 2007 BCEC -- 210B, Oral
Division of Medicinal Chemistry |