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100 years of sickle cell disease research: etiology, pathophysiology and rational drug design (part 1)
Beni-Suef University Journal of Basic and Applied Sciences Pub Date : 2019-12-01 , DOI: 10.1186/s43088-019-0016-x
Mona A. Mahran , Mohamed Teleb Ismail , Elwy H. Abdelkader

Sickle cell disease (SCD) is a chronic hemolytic disease caused by an altered hemoglobin molecule (HbS) and was first termed as a molecular disease. Glutamic acid in the normal hemoglobin molecule (HbA), was replaced by valine in HbS at the sixth position of both β-chains. This alteration was proved to be due to a single point mutation GTG instead of GAG in the genetic code. Since the discovery of sickle cell disease in 1910, great efforts have been done to study this disease on a molecular level. These efforts aimed to identify the disease etiology, pathophysiology, and finally to discover efficient treatment. Despite the tremendous work of many research groups all over the world, the only approved drug up to this moment, for the treatment of SCD is the hydroxyurea. In this review, the antisickling pharmaco-therapeutics will be classified into two major groups: hemoglobin site directed modifiers and ex-hemoglobin effectors. The first class will be discussed in details, here in, focusing on the most important figures in the way of the rational drug design for SCD treatment aiming to help scientists solve the mystery of this problem and to get clear vision toward possible required therapy for SCD. Despite the large number of the antisickling candidates that have been reached clinical studies yet, none of them has been introduced to the market. This may be due to the fact that hemoglobin is a large molecule with different target sites, which requires highly potent therapeutic agent. With this potency, these drugs should be safe, with acceptable oral pharmacokinetic and pharmacodynamic properties. Such ideal drug candidate needs more efforts to be developed.

中文翻译:

镰状细胞病研究 100 年:病因学、病理生理学和合理的药物设计(第 1 部分)

镰状细胞病 (SCD) 是一种由血红蛋白分子 (HbS) 改变引起的慢性溶血性疾病,最初被称为分子疾病。正常血红蛋白分子 (HbA) 中的谷氨酸在两条 β 链的第六位被 HbS 中的缬氨酸取代。这种改变被证明是由于遗传密码中的单点突变 GTG 而不是 GAG。自从 1910 年发现镰状细胞病以来,人们已经付出了巨大的努力在分子水平上研究这种疾病。这些努力旨在确定疾病的病因、病理生理学,并最终发现有效的治疗方法。尽管世界各地的许多研究小组做了大量工作,但迄今为止唯一获批用于治疗 SCD 的药物是羟基脲。在这次审查中,抗镰刀菌药物治疗剂将分为两大类:血红蛋白位点调节剂和前血红蛋白效应剂。第一堂课将详细讨论,在此重点介绍SCD治疗合理药物设计方式中最重要的数字,旨在帮助科学家解开这个问题的谜团,并对SCD可能需要的治疗方法有一个清晰的认识。 . 尽管有大量的抗镰刀菌候选药物已经进入临床研究,但没有一个被推向市场。这可能是因为血红蛋白是一个大分子,具有不同的靶点,需要高效的治疗剂。凭借这种效力,这些药物应该是安全的,具有可接受的口服药代动力学和药效学特性。
更新日期:2019-12-01
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