A novel compound active against SARS-CoV-2 targeting uridylate-specific endoribonuclease (NendoU/NSP15): in silico and in vitro investigations,RSC Medicinal Chemistry

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A novel compound active against SARS-CoV-2 targeting uridylate-specific endoribonuclease (NendoU/NSP15): in silico and in vitro investigations
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-08-18 , DOI: 10.1039/d1md00202c
Sumit Kumar ₁ , Yash Gupta ₂ , Samantha E Zak _{3,

4} , Charu Upadhyay ₁ , Neha Sharma ₅ , Andrew S Herbert ₃ , Ravi Durvasula ₂ , Vladimir Potemkin ₆ , John M Dye _{3,

4} , Poonam ₁ , Prakasha Kempaiah ₂ , Brijesh Rathi _{5,

6}

Affiliation

NendoU (NSP15) is an Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2′-3′-cyclic phosphates 5′ to the cleaved bond. Our in-house library was subjected to high throughput virtual screening (HTVS) to identify compounds with potential to inhibit NendoU enzyme, high-rank compounds (those that bound to multiple target structures) were further subjected to 100 nanoseconds MD simulations. Among these, one was found to be bound highly stable within the active site of the NendoU protein structure. Here, we are reporting a derivative of piperazine based ‘(2S,3S)-3-amino-1-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-4-phenylbutan-2-ol’ (IV) from our in-house libraries having potential efficacy against SARS-CoV-2 in in vitro assays. This compound demonstrated inhibition of viral replication at the same level as Ivermectin, a known SARS-CoV-2 inhibitor, which is not used due to its toxicity at a higher than the currently approved dosage. Compound IV was not toxic to the cell lines up to a 50 μM concentration and exhibited IC_50s of 4.97 μM and 8.46 μM in viral entry and spread assay, respectively. Therefore, this novel class of NendoU inhibitor could provide new insights for the development of treatment options for COVID-19.

中文翻译：

一种针对 SARS-CoV-2 靶向尿苷酸特异性核糖核酸内切酶 (NendoU/NSP15) 的新型化合物：计算机和体外研究

NendoU (NSP15) 是一种 Mn(2+) 依赖的尿苷酸特异性酶，它将 2'-3'-环状磷酸盐 5' 留在切割键上。我们的内部库进行了高通量虚拟筛选 (HTVS) 以识别具有抑制 NendoU 酶潜力的化合物，高级化合物（与多个目标结构结合的化合物）进一步进行 100 纳秒的 MD 模拟。其中，一个被发现在 NendoU 蛋白结构的活性位点内高度稳定地结合。在这里，我们报道了一种基于哌嗪的衍生物'(2 S ,3 S )-3-amino-1-(4-(4-( tert -butyl)benzyl)piperazine-1-yl)-4-phenylbutan-2 -ol' ( IV ) 来自我们的内部图书馆，对 SARS-CoV-2 具有潜在功效体外试验。这种化合物显示出与伊维菌素（一种已知的 SARS-CoV-2 抑制剂）相同水平的病毒复制抑制作用，由于其毒性高于目前批准的剂量，因此未被使用。化合物IV在高达 50 μM 的浓度下对细胞系没有毒性，并且在病毒进入和传播测定中分别表现出 4.97 μM 和 8.46 μM 的IC _{50 。}因此，这种新型 NendoU 抑制剂可以为 COVID-19 治疗方案的开发提供新的见解。

更新日期：2021-09-03

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