Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis
Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis
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DOI：
10.1016/j.ebiom.2020.102980
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发表时间：
2020-09-01
期刊：
影响因子：
11.1
通讯作者：
Hasnain, S. Samar
中科院分区：
文献类型：
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作者：
Amporndanai, Kangsa;Rogers, Michael;Hasnain, S. Samar
背景资料：肌萎缩侧索硬化症（ALS），也称为运动神经元疾病以及卢格里克病，是一种选择性影响运动神经元的进行性神经系统疾病，目前尚无治愈方法。大约20%的家族性ALS病例是由编码超氧化物歧化酶（SOD 1）的sod 1基因的显性突变引起的。家族性病例中突变型SOD 1的聚集和至少一些散发性ALS病例中野生型SOD 1的聚集是该疾病的已知原因之一。1995年批准的阿曲唑和2017年批准的依达拉奉仍然是唯一具有有限治疗益处的药物。方法：我们利用依布硒啉模板开发了新的化合物，这些化合物可以恢复突变SOD 1二聚体的稳定性并防止聚集。化合物的结合模式已经通过晶体学可视化。在体外神经保护和毒性的铅化合物已在小鼠神经元细胞和疾病的发病延迟已被证明在转基因ALS mice model.Finding：我们已经开发了一些ebselen为基础的化合物与改善A4 V SOD 1的稳定性和体外治疗效果，具有显着更好的效力比依达拉奉。命中的结构-活性关系已经由配体结合的A4 V SOD 1的高分辨率结构指导。我们还显示了明确的疾病发病延迟ebselen在转基因ALS小鼠模型举行令人鼓舞的承诺潜在的治疗compounds.Interpretation：我们的发现建立了新一代的有机硒化合物，具有更好的体外神经保护活性比依达拉奉。这类化合物的潜力可能为ALS治疗提供替代治疗剂。这些化合物靶向SOD中的半胱氨酸111的能力可能具有更广泛的治疗应用，靶向致病性和病毒性疾病中涉及的酶的半胱氨酸，包括SARS-Cov-2（COVID-19）的主要蛋白酶。(C)2020年，任作家。由爱思唯尔公司出版
Background: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding super-oxide dismutasel (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits.Methods: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model.Finding: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds.Interpretation: Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19). (C) 2020 The Authors. Published by Elsevier B.V.