5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells
5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells
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DOI：
10.1111/j.1365-2141.2004.05332.x
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发表时间：
2005-02-01
影响因子：
6.5
通讯作者：
Asakura, T
中科院分区：
文献类型：
--
作者：
Abdulmalik, O;Safo, MK;Asakura, T
为了寻找特异性结合细胞内镰状血红蛋白（HbS）而不受血浆和组织蛋白抑制或其他不良后果的新型抗镰状化剂，我们鉴定了5-羟甲基-2-糠醛（5 HMF），一种天然存在的芳香醛，作为满足这一标准的试剂。体外初步研究表明，5 HMF与HbS形成高亲和力的希夫碱加合物，并通过变构性地将氧平衡曲线向左移动来抑制红细胞镰状化。对转基因（Tg）镰状小鼠的进一步研究表明，口服给药的5 HMF从胃肠道迅速吸收到血流中而不被破坏，穿过红细胞膜，并以高达90%的水平特异性结合并修饰HbS分子。与未处理的小鼠相比，用5 HMF预处理Tg镰状小鼠抑制镰状细胞的形成，并显著延长在严重缺氧下的存活时间，未处理的小鼠在15分钟内因镰状依赖性肺隔离而死亡。这些结果表明5 HMF作为治疗镰状细胞病的有吸引力的潜在候选物的可行性。
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.