急性早幼粒细胞白血病（APL）是急性粒细胞白血病(AML)中恶性程度最高的特殊亚型。虽然全反式维甲酸（ATRA）联合蒽环类药物的治疗方案可以使90％左右的初治APL病人获得完全缓解，但仍有10％～15％的复发率,且复发后没有好的治疗方法。我们实验室最近的研究成果发现一种天然小分子化合物腺花素（Adenanthin），可以通过特异性修饰过氧化物氧还酶（Peroxiredoxins,Prxs）1和2上保守的半胱氨酸，抑制它们的过氧化物氧还酶活性，从而上调H2O2和C/EBP，最终诱导APL细胞分化，因此它有可能成为治疗耐ATRA早幼粒白血病的一种新型的药物。本研究项目将通过生物化学和结构生物学的手段，研究腺花素和Prxs特异性地相互作用的结构机制，揭示它是如何先结合于Prxs分子表面然后共价修饰其特异的半胱氨酸，同时，尝试改造Adenanthin并设计新型Prxs的小分子抑制剂。

Emerging data have implicated the potential of peroxiredoxins (Prxs), a family of peroxidases that reduce peroxides, as therapeutic targets for many diseases such as cancers, cardiovascular dysfunction, diabetes mellitus and neurodegeneration. Our recent study has discovered that adenanthin, a diterpenoid isolated from the leaves of Rabdosia adenantha, can specifically bind to the conserved resolving cysteines of Prx 1/2 and inhibits their peroxidase activity, thus result elevated levels of H2O2 and CCAAT/enhancer binding protein beta (C/EBPβ) in cell, which ultimately induces differentiation of acute promyelocytic leukemia (APL) cells in an all-trans retinoid acid (ATRA)-independent manner. Our proposed research project will focus on the molecular mechanism of how adenanthin specifically binds and inhibits Prx 1/2 activity and how we can modify adenanthin to increase its specificity and efficacy of towards Prx1/2. These studies will also shed lights on the development of new chemical compounds targeting Prxs for the treatment of various diseases.