An Activation-Specific Platelet Inhibitor That Can Be Turned On/Off by Medically Used Hypothermia Academic Article uri icon

abstract

  • OBJECTIVE: Therapeutic hypothermia is successfully used, for example, in cardiac surgery to protect organs from ischemia. Cardiosurgical procedures, especially in combination with extracorporeal circulation, and hypothermia itself are potentially prothrombotic. Despite the obvious need, the long half-life of antiplatelet drugs and thus the risk of postoperative bleedings have restricted their use in cardiac surgery. We describe here the design and testing of a unique recombinant hypothermia-controlled antiplatelet fusion protein with the aim of providing increased safety of hypothermia, as well as cardiac surgery. METHODS AND RESULTS: An elastin-mimetic polypeptide was fused to an activation-specific glycoprotein (GP) IIb/IIIa-blocking single-chain antibody. In silico modeling illustrated the sterical hindrance of a β-spiral conformation of elastin-mimetic polypeptide preventing the single-chain antibody from inhibiting GPIIb/IIIa at 37°C. Circular dichroism spectra demonstrated reverse temperature transition, and flow cytometry showed binding to and blocking of GPIIb/IIIa at hypothermic body temperature (≤32°C) but not at normal body temperature. In vivo thrombosis in mice was selectively inhibited at hypothermia but not at 37°C. CONCLUSIONS: This is the first description of a broadly applicable pharmacological strategy by which the activity of a potential drug can be controlled by temperature. In particular, this drug steerability may provide substantial benefits for antiplatelet therapy.

authors

  • Topcic, Denijal
  • Kim, Wookhyun
  • Holien, Jessica K
  • Jia, Fu
  • Armstrong, Paul C
  • Hohmann, Jan David
  • Straub, Andreas
  • Krippner, Guy
  • Haller, Carolyn A
  • Domeij, Helena
  • Hagemeyer, Christoph E
  • Parker, Michael W
  • Chaikof, Elliot L
  • Peter, Karlheinz

publication date

  • September 2011