Modulating hemoglobin allostery for treatment of sickle cell disease: current progress and intellectual property.
Modulating hemoglobin allostery for treatment of sickle cell disease: current progress and intellectual property.
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DOI：
10.1080/13543776.2022.1994945
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发表时间：
2022-03
影响因子：
6.6
通讯作者：
Safo MK
中科院分区：
文献类型：
--
作者：
Pagare PP;Rastegar A;Abdulmalik O;Omar AM;Zhang Y;Fleischman A;Safo MK
镰状细胞病（SCD）是一种使人衰弱的遗传性疾病，影响着全世界数百万人。四种新的SCD治疗药物已被批准，包括血红蛋白（Hb）调节剂voxelotor。这篇综述概述了在调节Hb变构行为作为SCD治疗方面的发现努力，重点是芳香醛增加Hb氧亲和力，以防止缺氧诱导的红细胞镰状细胞的主要病理生理。开发小分子，特别是芳香醛，以调节SCD的Hb变构特性的探索始于20世纪70年代；然而，早期的承诺受到了一些担忧的困扰，这些担忧阻碍了对研究工作的支持。坚持不懈的努力最终在2000年代发现了抗镰状细胞因子5-HMF，并重新激发了人们的兴趣，导致香兰素类似物的发现，包括FDA批准的首个用于治疗SCD的Hb调节剂voxelotor。随着人们对血红蛋白调节领域的兴趣日益浓厚，知识产权领域也在不断发展，包括处于临床前和临床研究各个阶段的候选药物。Hb调节剂不仅可以为SCD的高效口服治疗提供最佳机会，特别是在欠发达国家，而且还可以治疗各种其他人类疾病。
Sickle cell disease (SCD) is a debilitating inherited disorder that affects millions worldwide. Four novel SCD therapeutics have been approved, including the hemoglobin (Hb) modulator voxelotor. This review provides an overview of discovery efforts towards modulating Hb allosteric behavior as a treatment for SCD, with a focus on aromatic aldehydes that increase Hb oxygen affinity to prevent the primary pathophysiology of hypoxia-induce erythrocyte sickling. The quest to develop small molecules, especially aromatic aldehydes, to modulate Hb allosteric properties for SCD began in the 1970s; however, early promise was dogged by concerns that stalled support for research efforts. Persistent efforts eventually culminated in the discovery of the anti-sickling agent 5-HMF in the 2000s, and reinvigorated interest that led to the discovery of vanillin analogs, including voxelotor, the first FDA approved Hb modulator for the treatment of SCD. With burgeoning interest in the field of Hb modulation, there is a growing landscape of intellectual property, including drug candidates at various stages of preclinical and clinical investigations. Hb modulators could provide not only the best chance for a highly effective oral therapy for SCD, especially in the under-developed world, but also a way to treat a variety of other human conditions.
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影响因子：
6.5
作者：
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