De novo design of self-assembling foldamers that inhibit heparin-protein interactions

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

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

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 -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-factor Xa assay, showing their potential as heparin reversal agents.

Original languageEnglish (US)
Pages (from-to)967-975
Number of pages9
JournalACS Chemical Biology
Volume9
Issue number4
DOIs
StatePublished - Apr 18 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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