Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Nat Commun. 2018 Oct 23;9(1):4399. doi: 10.1038/s41467-018-06703-2.
Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.
泛酸激酶（PANK）是一种代谢酶，可调节细胞辅酶 A（CoA）水平。人类有三种 PANK 基因，PANK2 的失活突变导致泛酸激酶相关神经退行性变（PKAN）。在这里，我们进行了文库筛选，然后进行化学优化，得到了能够穿过血脑屏障的别构 PANK 激活剂 PZ-2891。PZ-2891 占据泛酸口袋，并与二聚体界面结合，形成 PANK•ATP•Mg•PZ-2891 复合物。PZ-2891 与一个单体的结合将另一个单体锁定在一种对乙酰辅酶 A 抑制作用具有抗性的催化活性构象中。PZ-2891 的口服给药可增加小鼠肝脏和大脑中的 CoA 水平。脑 CoA 缺乏症的基因敲除小鼠表现出体重减轻、严重运动障碍和早期死亡。接受 PZ-2891 治疗的基因敲除小鼠体重增加，运动能力提高，寿命延长，证明了 pantazines 是治疗 PKAN 的新型治疗药物。
