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Identification of a small molecule that increases hemoglobin oxygen affinity and reduces SS erythrocyte sickling.

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Nakagawa A, Lui FE, Wassaf D, Yefidoff-Freedman R, Casalena D, Palmer MA, Meadows J, Mozzarelli A, Ronda L, Abdulmalik O, Bloch KD, Safo MK, Zapol WM
OpenAccess logo ACS Chem Biol 9 2318-25 (2014)
Cited: 28 times
EuropePMC logo PMID: 25061917

Abstract

Small molecules that increase the oxygen affinity of human hemoglobin may reduce sickling of red blood cells in patients with sickle cell disease. We screened 38,700 compounds using small molecule microarrays and identified 427 molecules that bind to hemoglobin. We developed a high-throughput assay for evaluating the ability of the 427 small molecules to modulate the oxygen affinity of hemoglobin. We identified a novel allosteric effector of hemoglobin, di(5-(2,3-dihydro-1,4-benzodioxin-2-yl)-4H-1,2,4-triazol-3-yl)disulfide (TD-1). TD-1 induced a greater increase in oxygen affinity of human hemoglobin in solution and in red blood cells than did 5-hydroxymethyl-2-furfural (5-HMF), N-ethylmaleimide (NEM), or diformamidine disulfide. The three-dimensional structure of hemoglobin complexed with TD-1 revealed that monomeric units of TD-1 bound covalently to β-Cys93 and β-Cys112, as well as noncovalently to the central water cavity of the hemoglobin tetramer. The binding of TD-1 to hemoglobin stabilized the relaxed state (R3-state) of hemoglobin. TD-1 increased the oxygen affinity of sickle hemoglobin and inhibited in vitro hypoxia-induced sickling of red blood cells in patients with sickle cell disease without causing hemolysis. Our study indicates that TD-1 represents a novel lead molecule for the treatment of patients with sickle cell disease.

Reviews citing this publication (7)

  1. Therapeutic strategies for sickle cell disease: towards a multi-agent approach. Telen MJ, Malik P, Vercellotti GM. Nat Rev Drug Discov 18 139-158 (2019)
  2. Hemoglobin: Structure, Function and Allostery. Ahmed MH, Ghatge MS, Safo MK. Subcell Biochem 94 345-382 (2020)
  3. New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo? Oder E, Safo MK, Abdulmalik O, Kato GJ. Br J Haematol 175 24-30 (2016)
  4. Oxidative pathways in the sickle cell and beyond. Alayash AI. Blood Cells Mol Dis 70 78-86 (2018)
  5. Should modulation of p50 be a therapeutic target in the critically ill? Srinivasan AJ, Morkane C, Martin DS, Welsby IJ. Expert Rev Hematol 10 449-458 (2017)
  6. Modulating hemoglobin allostery for treatment of sickle cell disease: current progress and intellectual property. Pagare PP, Rastegar A, Abdulmalik O, Omar AM, Zhang Y, Fleischman A, Safo MK. Expert Opin Ther Pat 32 115-130 (2022)
  7. Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease. Olubiyi OO, Olagunju MO, Strodel B. Molecules 24 E4551 (2019)

Articles citing this publication (21)

  1. Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease. Li Q, Henry ER, Hofrichter J, Smith JF, Cellmer T, Dunkelberger EB, Metaferia BB, Jones-Straehle S, Boutom S, Christoph GW, Wakefield TH, Link ME, Staton D, Vass ER, Miller JL, Hsieh MM, Tisdale JF, Eaton WA. Proc Natl Acad Sci U S A 114 E689-E696 (2017)
  2. Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin. Henry ER, Metaferia B, Li Q, Harper J, Best RB, Glass KE, Cellmer T, Dunkelberger EB, Conrey A, Thein SL, Bunn HF, Eaton WA. Blood 138 1172-1181 (2021)
  3. Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin. Verespy S, Mehta AY, Afosah D, Al-Horani RA, Desai UR. Sci Rep 6 24043 (2016)
  4. Methemoglobin Formation and Characterization of Hemoglobin Adducts of Carcinogenic Aromatic Amines and Heterocyclic Aromatic Amines. Pathak KV, Chiu TL, Amin EA, Turesky RJ. Chem Res Toxicol 29 255-269 (2016)
  5. Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents. Omar AM, Mahran MA, Ghatge MS, Chowdhury N, Bamane FH, El-Araby ME, Abdulmalik O, Safo MK. Org Biomol Chem 13 6353-6370 (2015)
  6. Insights into the properties of the two enantiomers of trans-δ-viniferin, a resveratrol derivative: antioxidant activity, biochemical and molecular modeling studies of its interactions with hemoglobin. Ficarra S, Tellone E, Pirolli D, Russo A, Barreca D, Galtieri A, Giardina B, Gavezzotti P, Riva S, De Rosa MC. Mol Biosyst 12 1276-1286 (2016)
  7. Targeting βCys93 in hemoglobin S with an antisickling agent possessing dual allosteric and antioxidant effects. Kassa T, Strader MB, Nakagawa A, Zapol WM, Alayash AI. Metallomics 9 1260-1270 (2017)
  8. A Triazole Disulfide Compound Increases the Affinity of Hemoglobin for Oxygen and Reduces the Sickling of Human Sickle Cells. Nakagawa A, Ferrari M, Schleifer G, Cooper MK, Liu C, Yu B, Berra L, Klings ES, Safo RS, Chen Q, Musayev FN, Safo MK, Abdulmalik O, Bloch DB, Zapol WM. Mol Pharm 15 1954-1963 (2018)
  9. Antisickling Drugs Targeting βCys93 Reduce Iron Oxidation and Oxidative Changes in Sickle Cell Hemoglobin. Kassa T, Wood F, Strader MB, Alayash AI. Front Physiol 10 931 (2019)
  10. Development and validation of an oxygen dissociation assay, a screening platform for discovering, and characterizing hemoglobin-oxygen affinity modifiers. Patel MP, Siu V, Silva-Garcia A, Xu Q, Li Z, Oksenberg D. Drug Des Devel Ther 12 1599-1607 (2018)
  11. High-throughput determination of oxygen dissociation curves in a microplate reader-A novel, quantitative approach. Woyke S, Ströhle M, Brugger H, Strapazzon G, Gatterer H, Mair N, Haller T. Physiol Rep 9 e14995 (2021)
  12. Editorial Prospects for early investigational therapies for sickle cell disease. Conran N. Expert Opin Investig Drugs 24 595-602 (2015)
  13. Novel 4-Hydroxybenzyl Adducts in Human Hemoglobin: Structures and Mechanisms of Formation. Rajczewski AT, Ndreu L, Pujari SS, Griffin TJ, Törnqvist MÅ, Karlsson I, Tretyakova NY. Chem Res Toxicol 34 1769-1781 (2021)
  14. Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents. Omar AM, David T, Pagare PP, Ghatge MS, Chen Q, Mehta A, Zhang Y, Abdulmalik O, Naghi AH, El-Araby ME, Safo MK. Medchemcomm 10 1900-1906 (2019)
  15. An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling. Omar AM, Abdulmalik O, Ghatge MS, Muhammad YA, Paredes SD, El-Araby ME, Safo MK. Biomolecules 10 E1508 (2020)
  16. Aryloxyalkanoic Acids as Non-Covalent Modifiers of the Allosteric Properties of Hemoglobin. Omar AM, Mahran MA, Ghatge MS, Bamane FH, Ahmed MH, El-Araby ME, Abdulmalik O, Safo MK. Molecules 21 E1057 (2016)
  17. Design, Synthesis, and Biological Evaluation of Allosteric Effectors That Enhance CO Release from Carboxyhemoglobin. Goldstein SR, Liu C, Safo MK, Nakagawa A, Zapol WM, Winkler JD. ACS Med Chem Lett 9 714-718 (2018)
  18. The Relationship between APOL1 Structure and Function: Clinical Implications. Madhavan SM, Buck M. Kidney360 2 134-140 (2021)
  19. Atomic-Level View of the Functional Transition in Vertebrate Hemoglobins: The Case of Antarctic Fish Hbs. Balasco N, Paladino A, Graziano G, D'Abramo M, Vitagliano L. J Chem Inf Model 62 3874-3884 (2022)
  20. Drug discovery by a basic research scientist. Eaton WA. Front Mol Biosci 9 1062346 (2022)
  21. Kinetics of cyanide and carbon monoxide dissociation from ferrous human haptoglobin:hemoglobin(II) complexes. Ascenzi P, De Simone G, Tundo GR, Coletta M. J Biol Inorg Chem 25 351-360 (2020)


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