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

Authors


  • Part of this work was published in abstract form in Blood 2003: 102, 11 (part 1), abstract no. 922, and presented at the American Society of Hematology Annual Meeting, San Diego, CA, 2003.

  • EPA toxicity levels as well as data from previous investigations, including ours, do not imply Food and Drug Administration (FDA) approval for the use of 5HMF as an anti-sickling agent.

Dr Osheiza Abdulmalik, Division of Hematology, The Children's Hospital of Philadelphia, 3514 Civic Center Blvd., Philadelphia, PA 19104, USA.
E-mail: abdulmalik@email.chop.edu

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.

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