title: An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia.
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.
  
  
  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.affiliation: Atherothrombosis and Vascular Biology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Denijal
authors.initials: D
authors.lastname: Topcic
authors.forename: Wookhyun
authors.initials: W
authors.lastname: Kim
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Holien
authors.forename: Fu
authors.initials: F
authors.lastname: Jia
authors.forename: Paul C
authors.initials: PC
authors.lastname: Armstrong
authors.forename: Jan David
authors.initials: JD
authors.lastname: Hohmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Straub
authors.forename: Guy
authors.initials: G
authors.lastname: Krippner
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Haller
authors.forename: Helena
authors.initials: H
authors.lastname: Domeij
authors.forename: Christoph E
authors.initials: CE
authors.lastname: Hagemeyer
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: Elliot L
authors.initials: EL
authors.lastname: Chaikof
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
mesh_terms: D000818:Animals; D002942:Circular Dichroism; D001026:Coronary Artery Bypass; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007036:Hypothermia, Induced; D051379:Mice; D008958:Models, Molecular; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D014333:Tropoelastin / Q000008:administration & dosage*
chemical_list: D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D014333:Tropoelastin; D005340:Fibrinogen