title: 5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells.
abstract: 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.
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. abdulmalik@email.chop.edu
authors.forename: Osheiza
authors.initials: O
authors.lastname: Abdulmalik
authors.forename: Martin K
authors.initials: MK
authors.lastname: Safo
authors.forename: Qiukan
authors.initials: Q
authors.lastname: Chen
authors.forename: Jisheng
authors.initials: J
authors.lastname: Yang
authors.forename: Carlo
authors.initials: C
authors.lastname: Brugnara
authors.forename: Kwaku
authors.initials: K
authors.lastname: Ohene-Frempong
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Abraham
authors.forename: Toshio
authors.initials: T
authors.lastname: Asakura
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000517:prevention & control*; D000818:Animals; D000986:Antisickling Agents / Q000097:blood / Q000627:therapeutic use*; D001682:Biological Availability; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005662:Furaldehyde / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D006451:Hemoglobin, Sickle / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000860:Hypoxia / Q000150:complications; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D010101:Oxygen Consumption / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D000986:Antisickling Agents; D006451:Hemoglobin, Sickle; D008024:Ligands; C048065:5-methyl-2-furfural; D005662:Furaldehyde