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

ACS Chem Biol. 2014 Apr 18;9(4):967-75. doi: 10.1021/cb500026x. Epub 2014 Feb 11.


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 β-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Circular Dichroism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacology
  • Heparin / chemistry*
  • Inhibitory Concentration 50
  • Models, Biological*
  • Molecular Structure
  • Protein Binding / drug effects
  • Protein Conformation


  • Fibrinolytic Agents
  • Heparin