De Novo Design of Self-Assembling Foldamers That Inhibit Heparin–Protein Interactions

• DOI: 10.1021/cb500026x
• Publication Date: 2014-02-03T15:17:59Z
• Authors: Geronda L. Montalvo; Yao Zhang; Trevor M. Young; Michael J. Costanzo; Katie B. Freeman; Jun Wang; Dylan J. Clements; Emma Magavern; Robert W. Kavash; Richard W. Scott; Dahui Liu; William F. DeGrado
• Keywords: Foldamer; Random hexamer

A series of self-associating foldamers have been designed as heparin reversal agents, antidotes to prevent bleeding due this potent antithrombotic agent. The a repeating sequence Lys-Sal, in which Sal is 5-amino-2-methoxy-benzoic acid. These are self-associate along one face an extended chain β-sheet-like interaction. methoxy groups were included form intramolecular hydrogen bonds that preclude the formation very large amyloid-like aggregates, while positively charged Lys side chains introduced interact electrostatically with highly anionic polymer. prototype compound (Lys-Sal)4 carboxamide weakly associates aqueous solution at physiological salt concentration monomer-dimer-hexamer equilibrium. association greatly enhanced either high ionic strength or presence derivative, bound tightly. Variants foldamer active antithrombin III-factor Xa assay, showing their potential agents.