5‐hydroxymethyl‐2‐furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells

• Published in: British journal of haematology Vol. 128; no. 4; pp. 552 - 561
• Main Authors: Abdulmalik, Osheiza, Safo, Martin K., Chen, Qiukan, Yang, Jisheng, Brugnara, Carlo, Ohene‐Frempong, Kwaku, Abraham, Donald J., Asakura, Toshio
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.02.2005; Blackwell; Blackwell Publishing Ltd
• Subjects: Anemia, Sickle Cell - complications; Anemia, Sickle Cell - prevention & control; Anemias. Hemoglobinopathies; Animals; Antisickling Agents - blood; Antisickling Agents - therapeutic use; Biological and medical sciences; Biological Availability; Cells, Cultured; Diseases of red blood cells; Dose-Response Relationship, Drug; Erythrocytes - drug effects; Erythrocytes - metabolism; Furaldehyde - analogs & derivatives; Furaldehyde - blood; Furaldehyde - therapeutic use; Hematologic and hematopoietic diseases; Hematology; Hemoglobin, Sickle - chemistry; Hemoglobin, Sickle - drug effects; Hemoglobin, Sickle - metabolism; Hypoxia - complications; Ligands; Medical sciences; Mice; Mice, Transgenic; Models, Molecular; oxygen affinity; Oxygen Consumption - drug effects; pharmacokinetics; sickle cell disease; Survival Analysis; therapy; transgenic mice models; Hemoglobinopathy; Animal model; Sickle cell anemia; Hematology; transgenic mice models; therapy; Rodentia; Transgenic animal; Red blood cell; Hemopathy; Oxygen affinity; Genetic disease; sickle cell disease; Blood cell; Vertebrata; Hemolytic anemia; Mammalia; Treatment; Mouse; Hemoglobin; Inhibitor; Intracellular; Pharmacokinetics
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2004.05332.x

Summary In an attempt to find new types of anti‐sickling agents that specifically bind to intracellular sickle haemoglobin (HbS) without inhibition by plasma and tissue proteins or other undesirable consequences, we identified 5‐hydroxymethyl‐2‐furfural (5HMF), a naturally occurring aromatic aldehyde, as an agent that fulfils this criterion. Preliminary studies in vitro showed that 5HMF forms a high‐affinity Schiff‐base adduct with HbS and inhibits red cell sickling by allosterically shifting oxygen equilibrium curves towards the left. Further studies with transgenic (Tg) sickle mice showed that orally administered 5HMF was rapidly absorbed into the bloodstream from the gastrointestinal tract without being destroyed, traversed the red blood cell membrane and specifically bound with, and modified, HbS molecules at levels as high as 90%. Pretreatment of Tg sickle mice with 5HMF inhibited the formation of sickle cells and significantly prolonged survival time under severe hypoxia, compared with untreated mice, which died within 15 min because of sickling‐dependent pulmonary sequestration. These results indicate the feasibility of 5HMF as an attractive potential candidate for therapy of sickle cell disease.