An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 ?-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. Conclusion-: 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.
Original languageEnglish
Pages (from-to)2015 - 2023
Number of pages9
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume31
Issue number9
DOIs
Publication statusPublished - 2011
Externally publishedYes

Cite this

Topcic, Denijal ; Kim, Wookhyun ; Holien, Jessica K ; Jia, Fu ; Armstrong, Paul ; Hohmann, Jan David ; Straub, Andreas ; Krippner, Guy Yeoman ; Haller, Carolyn A ; Domeij, Helena ; Hagemeyer, Christoph Eugen ; Parker, Michael William ; Chaikof, Elliot L ; Peter, Karlheinz. / An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia. In: Arteriosclerosis, Thrombosis and Vascular Biology. 2011 ; Vol. 31, No. 9. pp. 2015 - 2023.
@article{52ecc9f5adab4b5f95b2faefe5122f72,
title = "An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia",
abstract = "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 ?-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. Conclusion-: 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.",
author = "Denijal Topcic and Wookhyun Kim and Holien, {Jessica K} and Fu Jia and Paul Armstrong and Hohmann, {Jan David} and Andreas Straub and Krippner, {Guy Yeoman} and Haller, {Carolyn A} and Helena Domeij and Hagemeyer, {Christoph Eugen} and Parker, {Michael William} and Chaikof, {Elliot L} and Karlheinz Peter",
year = "2011",
doi = "10.1161/ATVBAHA.111.226241",
language = "English",
volume = "31",
pages = "2015 -- 2023",
journal = "Arteriosclerosis, Thrombosis and Vascular Biology",
issn = "1079-5642",
publisher = "American Heart Association",
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Topcic, D, Kim, W, Holien, JK, Jia, F, Armstrong, P, Hohmann, JD, Straub, A, Krippner, GY, Haller, CA, Domeij, H, Hagemeyer, CE, Parker, MW, Chaikof, EL & Peter, K 2011, 'An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia' Arteriosclerosis, Thrombosis and Vascular Biology, vol. 31, no. 9, pp. 2015 - 2023. https://doi.org/10.1161/ATVBAHA.111.226241

An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia. / Topcic, Denijal; Kim, Wookhyun; Holien, Jessica K; Jia, Fu; Armstrong, Paul; Hohmann, Jan David; Straub, Andreas; Krippner, Guy Yeoman; Haller, Carolyn A; Domeij, Helena; Hagemeyer, Christoph Eugen; Parker, Michael William; Chaikof, Elliot L; Peter, Karlheinz.

In: Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 31, No. 9, 2011, p. 2015 - 2023.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia

AU - Topcic, Denijal

AU - Kim, Wookhyun

AU - Holien, Jessica K

AU - Jia, Fu

AU - Armstrong, Paul

AU - Hohmann, Jan David

AU - Straub, Andreas

AU - Krippner, Guy Yeoman

AU - Haller, Carolyn A

AU - Domeij, Helena

AU - Hagemeyer, Christoph Eugen

AU - Parker, Michael William

AU - Chaikof, Elliot L

AU - Peter, Karlheinz

PY - 2011

Y1 - 2011

N2 - 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 ?-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. Conclusion-: 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.

AB - 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 ?-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. Conclusion-: 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.

UR - http://atvb.ahajournals.org/content/31/9/2015

U2 - 10.1161/ATVBAHA.111.226241

DO - 10.1161/ATVBAHA.111.226241

M3 - Article

VL - 31

SP - 2015

EP - 2023

JO - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

SN - 1079-5642

IS - 9

ER -