Design of Nonhypertensive Conjugated Hemoglobins as Novel Resuscitation Fluids

Acharya, Seetharama A.; Intaglietta, Marcos; Tsai, Amy G.; Meng, Fantao

doi:10.1007/978-3-642-40717-8_11

Cited by 3 publications

(3 citation statements)

References 111 publications

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“…Consequently, only a trace amount of Hb–PEG–Hb appeared. Acharya et al reported that a shorter 600 Da mal 2 -PEG tends to generate Hb–PEG–Hb and oligomers through a stepwise reaction, and that of a 2 kDa mal 2 -PEG preferentially generates a thermodynamically stable monomeric Hb with a ring structure because it has suitable length only for intramolecular binding of two β93Cys thiol groups …”

Section: Discussionmentioning

confidence: 99%

Ring-Opening Polymerization of Hemoglobin

2019

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Hemoglobin (Hb), an oxygen-carrying protein, has an α2β2 tetrameric structure that dissociates reversibly into two αβ dimers (α 2β2 ⇄ 2αβ). We synthesized a cyclic Hb-ring monomer with two β subunits bound through a 10 kDa PEG chain. The monomer induced ringopening polymerization to produce a supramolecular polymer via inter-subunit interaction of αβ dimers of an Hb molecule at the PEG terminals. Both the ring-closed monomer and the ringopened supramolecular polymer were then fixed covalently by intramolecular crosslinking of two β subunits. Quantification of fixed products at various monomer concentrations revealed the equilibrium constant (K), a ratio of propagation and depropagation rate constants, as 5.68 mM −1 .The average degree of polymerization (DP �� ) increased proportionally, concomitantly with the initial monomer concentration. Hb polymer with DP �� = 13.2 (Mn = ca. 1 MDa) was obtained by crosslinking at 2.33 mM. Our novel strategy of ring-opening polymerization of Hb will eventually realize a highly aligned and efficiently polymerized Hb for creating artificial oxygen carriers for a clinical use.

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Section: Discussionmentioning

confidence: 99%

Ring-Opening Polymerization of Hemoglobin

2019

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“…It dissociates in the presence of 0.5–1.0 M MgCl 2 . , Generally, native Hb maintains tetrameric structures over the concentration of 0.1 mM at pH 7.4 and dissociates at lower concentrations such as 5 μM . Reportedly, PEGylation promotes dissociation of the α 2 β 2 tetramer. ,, An earlier study demonstrated that the dissociation constants of α 2 β 2 tetramer into dimers ( K d ) are 8.5 μM for native Hb, 10.5 μM for 5 kDa bis-PEGylated Hb, and 43.2 μM for 5 kDa multiple-PEGylated Hb with 6 PEG chains in the average (hexa-PEGylated-Hb), although it was not described how the K d values were measured. The tetrameric structure of hexa-PEGylated Hb is stable at a higher concentration of 800 μM in both anaerobic and aerobic conditions at pH 7.…”

Section: Discussionmentioning

confidence: 99%

“…The K d values were also reported for multiple PEGylated Hbs. The α 2 β 2 structure showed almost equal stability to that of native Hb up to hexa-PEGylation . However, the stability of the α 2 β 2 tetramer of native and PEGylated Hbs decreases in highly acidic and basic conditions, or in a diluted and an aerobic condition .…”

Section: Introductionmentioning

confidence: 94%

Analysis of Dimeric αβ Subunit Exchange between PEGylated and Native Hemoglobins (α₂β₂ Tetramer) in an Equilibrated State by Intramolecular ββ-Cross-Linking

et al. 2018

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Various chemical modifications of hemoglobin (Hb) including PEGylation have been investigated to produce red blood cell substitutes. Some of those modifications are designed on the premise that the αβ tetrameric structure of Hb is fundamentally stable and that it rarely dissociates into two αβ dimers in a physiological condition. However, in the present work using the "clipping" method we detected and quantitatively analyzed the considerable degree of exchange reaction of αβ subunits between β93Cys-bis-PEGylated and native Hbs through dissociation into αβ dimers and restructuring to αβ tetramer in a physiological condition. The equilibrium constant ( K) of subunit exchange reactions increased from 0.82 to 2.86 with increasing molecular weight of PEG from 2 to 40 kDa, indicating that longer PEG chains enhanced such exchange reaction. The results suggest that the exchange might occur for other modified Hbs even at a practically high concentration for use as a red blood cell substitute.

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Semisynthetic supra plasma expanders: a new class of therapeutics to improve microcircualtion in sickle cell anaemia

Meng

Kaul

Thangaswamy

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Design of Nonhypertensive Conjugated Hemoglobins as Novel Resuscitation Fluids

Cited by 3 publications

References 111 publications

Ring-Opening Polymerization of Hemoglobin

Ring-Opening Polymerization of Hemoglobin

Analysis of Dimeric αβ Subunit Exchange between PEGylated and Native Hemoglobins (α₂β₂ Tetramer) in an Equilibrated State by Intramolecular ββ-Cross-Linking

Semisynthetic supra plasma expanders: a new class of therapeutics to improve microcircualtion in sickle cell anaemia

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Design of Nonhypertensive Conjugated Hemoglobins as Novel Resuscitation Fluids

Cited by 3 publications

References 111 publications

Ring-Opening Polymerization of Hemoglobin

Ring-Opening Polymerization of Hemoglobin

Analysis of Dimeric αβ Subunit Exchange between PEGylated and Native Hemoglobins (α2β2 Tetramer) in an Equilibrated State by Intramolecular ββ-Cross-Linking

Semisynthetic supra plasma expanders: a new class of therapeutics to improve microcircualtion in sickle cell anaemia

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Analysis of Dimeric αβ Subunit Exchange between PEGylated and Native Hemoglobins (α₂β₂ Tetramer) in an Equilibrated State by Intramolecular ββ-Cross-Linking