De novo design of self-assembling foldamers that inhibit heparin-protein interactions.
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.
Department of Biochemistry & Biophysics and ‡Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
Geronda L
GL
Montalvo
Yao
Y
Zhang
Trevor M
TM
Young
Michael J
MJ
Costanzo
Katie B
KB
Freeman
Jun
J
Wang
Dylan J
DJ
Clements
Emma
E
Magavern
Robert W
RW
Kavash
Richard W
RW
Scott
Dahui
D
Liu
William F
WF
Degrado
D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006493:Heparin / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation
D005343:Fibrinolytic Agents; D006493:Heparin