De Novo Design of Self-Assembling Foldamers That Inhibit Heparin鈥揚rotein Interactions

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• 作者：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
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：April 18, 2014
• 年：2014
• 卷：9
• 期：4
• 页码：967-975
• 全文大小：514K
• 年卷期：v.9,no.4(April 18, 2014)
• ISSN：1554-8937

文摘

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