PMID- 38537246
OWN - NLM
STAT- Publisher
LR  - 20240517
IS  - 2192-2659 (Electronic)
IS  - 2192-2640 (Linking)
DP  - 2024 Mar 27
TI  - External Trigger Free Charge Switchable Cationic Ligands in the Design of Safe 
      and Effective Universal Heparin Antidote.
PG  - e2400108
LID - 10.1002/adhm.202400108 [doi]
AB  - Thrombosis, the formation of blood clots within a blood vessel, can lead to 
      severe complications including pulmonary embolism, cardiac arrest, and stroke. 
      The most widely administered class of anticoagulants is heparin-based 
      anticoagulants such as unfractionated heparin, low-molecular weight heparins 
      (LMWHs), and fondaparinux. Protamine is the only FDA-approved heparin antidote. 
      Protamine has limited efficacy neutralizing LMWHs and no reversal activity 
      against fondaparinux. The use of protamine can lead to complications, including 
      excessive bleeding, hypotension, and hypersensitivity, and has narrow therapeutic 
      window. In this work, a new concept in the design of a universal heparin 
      antidote: switchable protonation of cationic ligands, is presented. A library of 
      macromolecular polyanion inhibitors (MPIs) is synthesized and screened to 
      identify molecules that can neutralize all heparins with high selectivity and 
      reduced toxicity. MPIs are developed by assembling cationic binding groups 
      possessing switchable protonation states onto a polymer scaffold. By 
      strategically selecting the identity and modulating the density of cationic 
      binding groups on the polymer scaffold, a superior universal heparin reversal 
      agent is developed with improved heparin-binding activity and increased 
      hemocompatibility profiles leading to minimal effect on hemostasis. The activity 
      of this heparin antidote is demonstrated using in vitro and in vivo studies.
CI  - (c) 2024 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.
FAU - La, Chanel C
AU  - La CC
AD  - Centre for Blood Research, Life Sciences Institute, University of British 
      Columbia, Vancouver, BC, V6T 1Z3, Canada.
AD  - Department of Chemistry, University of British Columbia, Vancouver, BC, V6T 1Z3, 
      Canada.
FAU - Smith, Stephanie A
AU  - Smith SA
AD  - Department of Biological Chemistry, University of Michigan Medical School, Ann 
      Arbor, MI, 48109, USA.
FAU - Kalathottukaren, Manu Thomas
AU  - Kalathottukaren MT
AD  - Centre for Blood Research, Life Sciences Institute, University of British 
      Columbia, Vancouver, BC, V6T 1Z3, Canada.
AD  - Department of Pathology and Laboratory Medicine, University of British Columbia, 
      Vancouver, BC, V6T 1Z3, Canada.
FAU - Haynes, Charles A
AU  - Haynes CA
AD  - Department of Chemical and Biological Engineering, University of British 
      Columbia, Vancouver, BC, V6T 1Z3, Canada.
AD  - Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 
      1Z3, Canada.
FAU - Morrissey, James H
AU  - Morrissey JH
AUID- ORCID: 0000-0002-1570-1569
AD  - Department of Biological Chemistry, University of Michigan Medical School, Ann 
      Arbor, MI, 48109, USA.
FAU - Kizhakkedathu, Jayachandran N
AU  - Kizhakkedathu JN
AUID- ORCID: 0000-0001-7688-7574
AD  - Centre for Blood Research, Life Sciences Institute, University of British 
      Columbia, Vancouver, BC, V6T 1Z3, Canada.
AD  - Department of Chemistry, University of British Columbia, Vancouver, BC, V6T 1Z3, 
      Canada.
AD  - Department of Pathology and Laboratory Medicine, University of British Columbia, 
      Vancouver, BC, V6T 1Z3, Canada.
LA  - eng
GR  - UM1 HL120877/HL/NHLBI NIH HHS/United States
GR  - R35 HL135823/HL/NHLBI NIH HHS/United States
GR  - CAPMC/CIHR/Canada
PT  - Journal Article
DEP - 20240327
PL  - Germany
TA  - Adv Healthc Mater
JT  - Advanced healthcare materials
JID - 101581613
SB  - IM
OTO - NOTNLM
OT  - blood coagulation
OT  - heparin neutralization
OT  - heparins
OT  - polymer design for biology
OT  - smart cationic polymers
EDAT- 2024/03/28 00:44
MHDA- 2024/03/28 00:44
CRDT- 2024/03/27 18:02
PHST- 2024/03/06 00:00 [revised]
PHST- 2024/01/10 00:00 [received]
PHST- 2024/03/28 00:44 [pubmed]
PHST- 2024/03/28 00:44 [medline]
PHST- 2024/03/27 18:02 [entrez]
AID - 10.1002/adhm.202400108 [doi]
PST - aheadofprint
SO  - Adv Healthc Mater. 2024 Mar 27:e2400108. doi: 10.1002/adhm.202400108.