Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin

Overview

Journal Hematol Oncol Clin North Am

Specialties Hematology
Oncology

Date 2014 Mar 5

PMID 24589263

Citations 38

Authors

Martin K Safo

Gregory J Kato

Affiliations

Soon will be listed here.

Abstract

The pathophysiology of sickle cell disease involves the polymerization of sickle hemoglobin in its T state, which develops under low oxygen saturation. One therapeutic strategy is to develop pharmacologic agents to stabilize the R state of hemoglobin, which has higher oxygen affinity and is expected to have slower kinetics of polymerization, potentially delaying the sickling of red cells during circulation. This strategy has stimulated the investigation of aromatic aldehydes, aspirin derivatives, thiols, and isothiocyanates that can stabilize the R state of hemoglobin in vitro. One representative aromatic aldehyde agent, 5-hydoxymethyl-2-furfural, protects sickle cell mice from the effects of hypoxia.

Citing Articles

Hemoglobin Variants as Targets for Stabilizing Drugs.

Zoldakova M, Novotny M, Khakurel K, Zoldak G Molecules. 2025; 30(2).

PMID: 39860253 PMC: 11767434. DOI: 10.3390/molecules30020385.

Effect of voxelotor on cerebral perfusion and cerebral oxygen metabolism and cardiac stress in adult patients with sickle cell disease.

Konte K, Afzali-Hashemi L, Baas K, Schrantee A, Wood J, Nur E Am J Hematol. 2024; 100(1):78-84.

PMID: 39564863 PMC: 11625979. DOI: 10.1002/ajh.27522.

Metabolic regulation of erythrocyte development and disorders.

Lyu J, Ni M, Weiss M, Xu J Exp Hematol. 2024; 131:104153.

PMID: 38237718 PMC: 10939827. DOI: 10.1016/j.exphem.2024.104153.

Peak nasal inspiratory flow in children and adolescents with sickle cell disease: a case-control study.

Vieira A, Alvim C, Braga C, Dinardi R, Borba M, Rodrigues R Rev Assoc Med Bras (1992). 2023; 69(10):e20210819.

PMID: 37792864 PMC: 10547482. DOI: 10.1590/1806-9282.20210819.

X-ray crystallography and sickle cell disease drug discovery-a tribute to Donald Abraham.

Donkor A, Pagare P, Mughram M, Safo M Front Mol Biosci. 2023; 10:1136970.

PMID: 37293554 PMC: 10244664. DOI: 10.3389/fmolb.2023.1136970.

References

Sheh L, Mokotoff M, Abraham D . Design, synthesis, and testing of potential antisickling agents. 9. Cyclic tetrapeptide homologs as mimics of the mutation site of hemoglobin S. Int J Pept Protein Res. 1987; 29(4):509-20. DOI: 10.1111/j.1399-3011.1987.tb02278.x. View

Beutler E, Paniker N, West C . The effect of 2,3-DPG on the sickling phenomenon. Blood. 1971; 37(2):184-6. View

Riggs A, Wells M . The oxygen equilibrium of sickle-cell hemoglobin. Biochim Biophys Acta. 1961; 50:243-8. DOI: 10.1016/0006-3002(61)90322-5. View

Matzi V, Lindenmann J, Muench A, Greilberger J, Juan H, Wintersteiger R . The impact of preoperative micronutrient supplementation in lung surgery. A prospective randomized trial of oral supplementation of combined alpha-ketoglutaric acid and 5-hydroxymethylfurfural. Eur J Cardiothorac Surg. 2007; 32(5):776-82. DOI: 10.1016/j.ejcts.2007.07.016. View

Wireko F, Abraham D . X-ray diffraction study of the binding of the antisickling agent 12C79 to human hemoglobin. Proc Natl Acad Sci U S A. 1991; 88(6):2209-11. PMC: 51199. DOI: 10.1073/pnas.88.6.2209. View

Yonetani T, Tsuneshige A . The global allostery model of hemoglobin: an allosteric mechanism involving homotropic and heterotropic interactions. C R Biol. 2003; 326(6):523-32. DOI: 10.1016/s1631-0691(03)00150-1. View

WALDER J, Zaugg R, Walder R, Steele J, KLOTZ I . Diaspirins that cross-link beta chains of hemoglobin: bis(3,5-dibromosalicyl) succinate and bis(3,5-dibromosalicyl) fumarate. Biochemistry. 1979; 18(20):4265-70. DOI: 10.1021/bi00587a001. View

Merrett M, Stammers D, White R, Wootton R, Kneen G . Characterization of the binding of the anti-sickling compound, BW12C, to haemoglobin. Biochem J. 1986; 239(2):387-92. PMC: 1147292. DOI: 10.1042/bj2390387. View

Park S, Hayes B, Marankan F, Mulhearn D, Wanna L, Mesecar A . Regioselective covalent modification of hemoglobin in search of antisickling agents. J Med Chem. 2003; 46(6):936-53. DOI: 10.1021/jm020361k. View

10.

Abraham D, Safo M, Boyiri T, Kister J, Poyart C . How allosteric effectors can bind to the same protein residue and produce opposite shifts in the allosteric equilibrium. Biochemistry. 1995; 34(46):15006-20. DOI: 10.1021/bi00046a007. View

11.

Patwa D, Abraham D, Hung T . Design, synthesis, and testing of potential antisickling agents. 6. Rheologic studies with active phenoxy and benzyloxy acids. Blood Cells. 1987; 12(3):589-601. View

12.

Keidan A, Franklin I, White R, Joy M, Huehns E, Stuart J . Effect of BW12C on oxygen affinity of haemoglobin in sickle-cell disease. Lancet. 1986; 1(8485):831-4. DOI: 10.1016/s0140-6736(86)90941-4. View

13.

Zhang C, Li X, Lian L, Chen Q, Abdulmalik O, Vassilev V . Anti-sickling effect of MX-1520, a prodrug of vanillin: an in vivo study using rodents. Br J Haematol. 2004; 125(6):788-95. DOI: 10.1111/j.1365-2141.2004.04892.x. View

14.

Wood W, Pembrey M, Serjeant G, PERRINE R, Weatherall D . Hb F synthesis in sickle cell anaemia: a comparison of Saudi Arab cases with those of African origin. Br J Haematol. 1980; 45(3):431-45. DOI: 10.1111/j.1365-2141.1980.tb07163.x. View

15.

Lukin J, Kontaxis G, Simplaceanu V, Yuan Y, Bax A, Ho C . Quaternary structure of hemoglobin in solution. Proc Natl Acad Sci U S A. 2003; 100(2):517-20. PMC: 141027. DOI: 10.1073/pnas.232715799. View

16.

Rolan P, Parker J, Gray S, Weatherley B, Ingram J, Leavens W . The pharmacokinetics, tolerability and pharmacodynamics of tucaresol (589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a potential anti-sickling agent, following oral administration to healthy subjects. Br J Clin Pharmacol. 1993; 35(4):419-25. PMC: 1381554. DOI: 10.1111/j.1365-2125.1993.tb04160.x. View

17.

Lalezari I, Lalezari P, Poyart C, Marden M, Kister J, Bohn B . New effectors of human hemoglobin: structure and function. Biochemistry. 1990; 29(6):1515-23. DOI: 10.1021/bi00458a024. View

18.

Rhoda M, Martin J, Blouquit Y, Garel M, Edelstein S, Rosa J . Sickle cell hemoglobin fiber formation strongly inhibited by the Stanleyville II mutation (alpha 78 Asn leads to Lys). Biochem Biophys Res Commun. 1983; 111(1):8-13. DOI: 10.1016/s0006-291x(83)80109-0. View

19.

Garel M, Domenget C, Galacteros F, Beuzard Y . Inhibition of erythrocyte sickling by thiol reagents. Mol Pharmacol. 1984; 26(3):559-65. View

20.

Perutz M, FERMI G, Luisi B, Shaanan B, Liddington R . Stereochemistry of cooperative mechanisms in hemoglobin. Cold Spring Harb Symp Quant Biol. 1987; 52:555-65. DOI: 10.1101/sqb.1987.052.01.063. View