PMID- 28880550
OWN - NLM
STAT- MEDLINE
DCOM- 20180524
LR  - 20181202
IS  - 1526-4602 (Electronic)
IS  - 1525-7797 (Linking)
VI  - 18
IP  - 10
DP  - 2017 Oct 9
TI  - A Polymer Therapeutic Having Universal Heparin Reversal Activity: Molecular 
      Design and Functional Mechanism.
PG  - 3343-3358
LID - 10.1021/acs.biomac.7b00994 [doi]
AB  - Heparins are widely used to prevent blood clotting during surgeries and for the 
      treatment of thrombosis. However, bleeding associated with heparin therapy is a 
      concern. Protamine, the only approved antidote for unfractionated heparin (UFH) 
      could cause adverse cardiovascular events. Here, we describe a unique molecular 
      design used in the development of a synthetic dendritic polycation named as 
      universal heparin reversal agent (UHRA), an antidote for all clinically used 
      heparin anticoagulants. We elucidate the mechanistic basis for the selectivity of 
      UHRA to heparins and its nontoxic nature. Isothermal titration calorimetry based 
      binding studies of UHRAs having different methoxypolyethylene glycol (mPEG) brush 
      structures with UFH as a function of solution conditions, including ionic 
      strength, revealed that mPEG chains impose entropic penalty to the electrostatic 
      binding. Binding studies confirm that, unlike protamine or N-UHRA (a truncated 
      analogue of UHRA with no mPEG chains), the mPEG chains in UHRA avert nonspecific 
      interactions with blood proteins and provide selectivity toward heparins through 
      a combined steric repulsion and Donnan shielding effect (a balance of F(el) and 
      F(steric)). Clotting assays reveal that UHRA with mPEG chains did not adversely 
      affect clotting, and neutralized UFH over a wide range of concentrations. 
      Conversely, N-UHRA and protamine display intrinsic anticoagulant activity and 
      showed a narrow concentration window for UFH neutralization. In addition, we 
      found that mPEG chains regulate the size of antidote-UFH complexes, as revealed 
      by atomic force microscopy and dynamic light scattering studies. UHRA molecules 
      with mPEG chains formed smaller complexes with UFH, compared to N-UHRA and 
      protamine. Finally, fluorescence and ELISA experiments show that UHRA disrupts 
      antithrombin-UFH complexes to neutralize heparin's activity.
FAU - Kalathottukaren, Manu Thomas
AU  - Kalathottukaren MT
AUID- ORCID: 0000-0001-5374-7114
AD  - Centre for Blood Research and Department of Pathology and Laboratory Medicine, 
      University of British Columbia , Vancouver, BC, Canada.
FAU - Abbina, Srinivas
AU  - Abbina S
AD  - Centre for Blood Research and Department of Pathology and Laboratory Medicine, 
      University of British Columbia , Vancouver, BC, Canada.
FAU - Yu, Kai
AU  - Yu K
AD  - Centre for Blood Research and Department of Pathology and Laboratory Medicine, 
      University of British Columbia , Vancouver, BC, Canada.
FAU - Shenoi, Rajesh A
AU  - Shenoi RA
AD  - Centre for Blood Research and Department of Pathology and Laboratory Medicine, 
      University of British Columbia , Vancouver, BC, Canada.
AD  - Centre for Drug Discovery, Inter University Centre for Biomedical Research & 
      Super Speciality Hospital , Kottayam, Kerala, India.
FAU - Creagh, A Louise
AU  - Creagh AL
AD  - Michael Smith Laboratories, Department of Chemical and Biological Engineering, 
      University of British Columbia , Vancouver, BC, Canada.
FAU - Haynes, Charles
AU  - Haynes C
AD  - Centre for Blood Research and Department of Pathology and Laboratory Medicine, 
      University of British Columbia , Vancouver, BC, Canada.
AD  - Michael Smith Laboratories, Department of Chemical and Biological Engineering, 
      University of British Columbia , Vancouver, BC, Canada.
FAU - Kizhakkedathu, Jayachandran N
AU  - Kizhakkedathu JN
AUID- ORCID: 0000-0001-7688-7574
AD  - Centre for Blood Research and Department of Pathology and Laboratory Medicine, 
      University of British Columbia , Vancouver, BC, Canada.
AD  - Department of Chemistry, University of British Columbia , Vancouver, BC, Canada.
LA  - eng
PT  - Journal Article
DEP - 20170919
PL  - United States
TA  - Biomacromolecules
JT  - Biomacromolecules
JID - 100892849
RN  - 0 (Anticoagulants)
RN  - 0 (Antidotes)
RN  - 0 (Blood Proteins)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 9004-74-4 (monomethoxypolyethylene glycol)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Anticoagulants/adverse effects/*chemical synthesis/chemistry
MH  - Antidotes/chemical synthesis/chemistry
MH  - Blood Coagulation
MH  - Blood Proteins/metabolism
MH  - Heparin/adverse effects/*analogs & derivatives
MH  - Humans
MH  - Osmolar Concentration
MH  - Polyethylene Glycols/chemistry
MH  - Protein Binding
MH  - Static Electricity
EDAT- 2017/09/08 06:00
MHDA- 2018/05/25 06:00
CRDT- 2017/09/08 06:00
PHST- 2017/09/08 06:00 [pubmed]
PHST- 2018/05/25 06:00 [medline]
PHST- 2017/09/08 06:00 [entrez]
AID - 10.1021/acs.biomac.7b00994 [doi]
PST - ppublish
SO  - Biomacromolecules. 2017 Oct 9;18(10):3343-3358. doi: 10.1021/acs.biomac.7b00994. 
      Epub 2017 Sep 19.