A quantitative framework for the design of acellular hemoglobins as blood substitutes: Implications of dynamic flow conditions

Cole, Russell H.; Vandegriff, Kim D.; Szeri, Andrew J.; Savaş, Ömer; Baker, Dawn; Winslow, Robert M.

doi:10.1016/j.bpc.2007.03.004

Cited by 20 publications

(32 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This analysis led to a reevaluation of the desirable properties for a safe and effective HBOC. These include increased oxygen affinity and high binding cooperativity, as well as defined structures, increased molecular size, and increased viscosity (41). The three bis-tetramers developed in this work possess all of the proposed properties, which make them very promising as potential HBOCs.…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Functional Cross-Linked Hemoglobin Bis-tetramers: Geometry and Cooperativity

Kluger

2008

Biochemistry

View full text Add to dashboard Cite

Hemoglobin-based oxygen carriers have been sought as stable, sterile alternatives to red cells in transfusions. Problems in clinical trials using cross-linked tetramers have led to proposals that larger assemblies of tetramers may alleviate some of the problems. A study of such assemblies requires materials with defined structures and physical properties. Evaluation of cross-linked bis-tetramers with inflexible linear links between the tetramers revealed that these have very low cooperativity in oxygen binding and would thus be inefficient as oxygen carriers. New, more flexible reagents were designed to cross-link and connect tetramers in two modes: with angular connectors that permit torsional movement (1-3) and with linear connectors that resemble previously studied systems (4-6). The resulting cross-linked bis-tetramers were produced in high yield and were isolated and characterized. Digest mapping showed that modifications were specifically introduced as expected at amino groups in the 2,3-bisphosphoglycerate binding sites within beta subunits. Circular dichroism showed that the secondary structure of the globin chains is maintained while the microenvironment of the hemes is altered. The bis-tetramers derived from 1-3 have oxygen affinity (P(50) = 3.6-4.7) and cooperativity (n(50) = 2.2-2.7) that appear to be suitable for efficient oxygen delivery to hypoxic regions along with increased mass that is expected to minimize extravasation.

show abstract

Section: Discussionmentioning

confidence: 94%

“…Transient proton movements between the carboxyl and amino groups facilitate acylation of the amino groups of the lysyl side chains (41).…”

Section: Discussionmentioning

confidence: 99%

Functional Cross-Linked Hemoglobin Bis-tetramers: Geometry and Cooperativity

Kluger

2008

Biochemistry

View full text Add to dashboard Cite

show abstract

“…Deer mice adapted to high altitude also carry Hb isoforms with higher intrinsic O 2 affinities (64). Furthermore, Cole et al (65) proposed a mathematical model for O 2 transport and postulated that cell-free oxygen carriers should have P 50 in the range of 5-15 mm Hg, which is higher or equivalent to that of Hb A. The rHb (␤V67F) in this study has an O 2 binding affinity higher than that of the ␣L29F mutant (Fig.…”

Section: Discussionmentioning

confidence: 97%

Autoxidation and Oxygen Binding Properties of Recombinant Hemoglobins with Substitutions at the αVal-62 or βVal-67 Position of the Distal Heme Pocket

Tam

Rice

Maillett

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Tertiary structure of the ligand binding pocket influences oxygen binding and autoxidation of hemoglobin. Results: E11 mutants have increased autoxidation rate. ␤E11Phe increases, whereas ␤E11Ile decreases the oxygen binding affinity of hemoglobin. Conclusion: Bulky residues at ␤E11 affect ligand binding and cause noticeable tertiary structural changes at the heme pockets. Significance: Hemoglobin distal heme pocket mutations alter oxygen binding properties without changing the quaternary structure.

show abstract

“…The presence of cell-free hemoglobin in the interstitial space is thought to further reduce the enzymatic NO availability and thus induce vasoconstriction [11,12], although the mechanism behind the vasoconstriction induced by this cell-free hemoglobin is under debate [36]. We compared the NO levels in the smooth muscle resulting from the cell-free hemoglobin/nitrite interaction alone, assuming that extravasation did or did not occur.…”

Section: Extravasation Of Cell-free Hemoglobin Into the Interstitial mentioning

confidence: 99%

Nitric oxide from nitrite reduction by hemoglobin in the plasma and erythrocytes

et al. 2008

View full text Add to dashboard Cite

Experimental evidence has shown that nitrite anion plays a key role in one of the proposed mechanisms for hypoxic vasodilation, in which the erythrocyte acts as a NO generator and deoxygenated hemoglobin in pre-capillary arterioles reduces nitrite to NO, which contributes to vascular smooth muscle relaxation. However, because of the complex reactions among nitrite, hemoglobin, and the NO that is formed, the amount of NO delivered by this mechanism under various conditions has not been quantified experimentally. Furthermore, paracrine NO is scavenged by cellfree hemoglobin, as shown by studies of diseases characterized by extensive hemolysis (e.g., sickle cell disease) and the administration of hemoglobin-based oxygen carriers. Taking into consideration the free access of cell-free hemoglobin to the vascular wall and its ability to act as a nitrite reductase, we have now examined the hypothesis that in hypoxia this cell-free hemoglobin could serve as an additional endocrine source of NO. In this study, we constructed a multicellular model to characterize the amount of NO delivered by the reaction of nitrite with both intraerythrocytic and cell-free hemoglobin, while intentionally neglecting all other possible sources of NO in the vasculature. We also examined the roles of hemoglobin molecules in each compartment as nitrite reductases and NO scavengers using the model. Our calculations show that: (1) ~0.04 pM NO from erythrocytes could reach the smooth muscle if free diffusion were the sole export mechanism; however, this value could rise to ~43 pM with a membrane-associated mechanism that facilitated NO release from erythrocytes; the results also strongly depend on the erythrocyte membrane permeability to NO; (2) despite the closer proximity of cell-free hemoglobin to the smooth muscle, cell-free hemoglobin reaction with nitrite generates approximately 0.02 pM of free NO that can reach the vascular wall, because of a strong self-capture effect. However, it is worth noting that this value is in the same range as erythrocytic hemoglobin-generated NO that is able to diffuse freely out of the cell, despite the tremendous difference in hemoglobin concentration in both cases (μM hemoglobin in plasma vs. mM in erythrocyte); (3) intraerythrocytic hemoglobin encapsulated by a NO-resistant membrane is the major source of NO from nitrite reduction, and cell-free hemoglobin is a significant scavenger of both paracrine and endocrine NO.* Corresponding

show abstract

A quantitative framework for the design of acellular hemoglobins as blood substitutes: Implications of dynamic flow conditions

Cited by 20 publications

References 46 publications

Functional Cross-Linked Hemoglobin Bis-tetramers: Geometry and Cooperativity

Functional Cross-Linked Hemoglobin Bis-tetramers: Geometry and Cooperativity

Autoxidation and Oxygen Binding Properties of Recombinant Hemoglobins with Substitutions at the αVal-62 or βVal-67 Position of the Distal Heme Pocket

Nitric oxide from nitrite reduction by hemoglobin in the plasma and erythrocytes

Contact Info

Product

Resources

About