Thrombin‐Inhibiting Anticoagulant Liposomes: Development and Characterization. Issue 3 (14th December 2015)

• Record Type: Journal Article
• Authors: Endreas, Wegderes; Brüßler, Jana; Vornicescu, Doru; Keusgen, Michael; Bakowsky, Udo; Steinmetzer, Torsten
• Is Part Of: ChemMedChem. Volume 11:Issue 3(2016)
• Page Start: 340
• Page End: 349
• Publication Date: 2015-12-14
• Subjects: anticoagulants -- inhibitors -- liposomes -- peptidomimetics -- thrombin; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500489
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Many peptides and peptidomimetic drugs suffer from rapid clearance in vivo; this can be reduced by increasing their size through oligomerization or covalent conjugation with polymers. As proof of principle, an alternative strategy for drug oligomerization is described, in which peptidomimetic thrombin inhibitors are incorporated into the liposome surface. For this purpose, the inhibitor moieties were covalently coupled to a palmitic acid residue through a short bifunctionalized ethylene glycol spacer. These molecules were directly added to the lipid mixture used for liposome preparation. The obtained liposomes possess strong thrombin inhibitory potency in enzyme kinetic measurements and anticoagulant activity in plasma. Their strong potency and positive ζ potential indicate that large amounts of the benzamidine‐derived inhibitors are located on the surface of the liposomes. This concept should be applicable to other drug molecules that suffer from rapid elimination and allow covalent modification with a suitable fatty acid residue. Abstract : New anticoagulant liposomes : Highly potent palmitoylated thrombin inhibitors were developed and conveniently incorporated into membranes during liposome preparation. The liposomes contain the inhibitor moiety on their surface and possess strong thrombin inhibitory potency and anticoagulant activity in plasma. This concept should be applicable to other drug molecules that suffer from rapid elimination and allow covalent modification with a suitable fatty acid residue.