Department of Cell Biology, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA, Rotterdam, The Netherlands.
Department of Chemistry, University of Marburg, Hans-Meerwein-Straβe 4, 35043, Marburg, Germany.
ChemMedChem. 2020 Dec 15;15(24):2436-2443. doi: 10.1002/cmdc.202000574. Epub 2020 Nov 4.
The level of fetal hemoglobin (HbF) is an important disease modifier for β-thalassemia and sickle cell disease patients. Indeed, genetic tinkering with the HbF repression machinery has demonstrated great potential for disease mitigation. Such genetic treatments are costly and the high incidence of β-hemoglobinopathies in low-income countries, therefore, calls for the development of affordable, off-the-shelf, oral treatments. The use of PROTAC (PRoteolysis TArgeting Chimeras) technology to influence the epigenetic mechanisms involved in HbF suppression may provide a solution. In this minireview, we briefly explain the HbF repression network highlighting the epigenetic factors that could be targeted for degradation by PROTACs. We hope that this review will inspire clinicians, molecular and chemical biologists to collaborate and contribute to this fascinating field, which should ultimately deliver drugs that reactivate HbF expression with high specificity and low toxicity.
胎儿血红蛋白 (HbF) 的水平是β-地中海贫血和镰状细胞病患者的重要疾病修饰因子。事实上，对 HbF 抑制机制的基因修饰已经显示出了在疾病缓解方面的巨大潜力。这种基因治疗成本高昂，而且低收入国家的β-血红蛋白病发病率很高，因此需要开发负担得起的、现成的、口服治疗方法。使用 PROTAC（蛋白水解靶向嵌合体）技术来影响参与 HbF 抑制的表观遗传机制可能是一种解决方案。在这篇综述中，我们简要解释了 HbF 抑制网络，重点介绍了可以通过 PROTAC 进行降解的表观遗传因素。我们希望这篇综述能够激发临床医生、分子和化学生物学家进行合作，为这一迷人的领域做出贡献，最终应该能够开发出具有高特异性和低毒性的、能够重新激活 HbF 表达的药物。
