Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: Synthesis and biological characterization.
Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: Synthesis and biological characterization.
复制标题
DOI：
10.1016/j.bioorg.2022.106198
复制
发表时间：
2022-12
影响因子：
5.1
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
He T;Edwards TC;Majima R;Jung E;Kankanala J;Xie J;Geraghty RJ;Wang Z
人巨细胞病毒（HCMV）的末端酶复合体是病毒基因组包装和切割所必需的。对末端酶功能至关重要的是pUL89 c端金属依赖的内切酶（pUL89- c）。我们之前报道过金属螯合n-羟基噻吩嘧啶-2,4-二酮（HtPD）作为人类免疫缺陷病毒1 (HIV-1) RNase h的抑制剂。在目前的工作中，我们合成了新的类似物，并重新合成了两种同分异构体HtPD亚型，anti-HtPD（13）和syn-HtPD(14)，并将它们表征为pUL89-C的抑制剂。值得注意的是，绝大多数类似物在生化核酸内切酶测定中强烈抑制pUL89-C， IC50值在nM范围内。在基于细胞的抗病毒实验中，一些类似物在低μM浓度下抑制HCMV。选择的类似物通过生物物理热移实验（TSA）和硅分子对接进一步表征，结果支持pUL89-C作为这些抑制剂的蛋白靶点。总之，本文报道的生化、抗病毒、生物物理和计算机数据表明，HtPD的同分异构体13-14化学型可以作为设计HCMV pUL89-C抑制剂的有价值的化学平台。
The terminase complex of human cytomegalovirus (HCMV) is required for viral genome packaging and cleavage. Critical to the terminase functions is a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C). We have previously reported metal-chelating N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human immunodeficiency virus 1 (HIV-1) RNase H. In the current work, we have synthesized new analogs and resynthesized known analogs of two isomeric HtPD subtypes, anti-HtPD (13), and syn-HtPD (14), and characterized them as inhibitors of pUL89-C. Remarkably, the vast majority of analogs strongly inhibited pUL89-C in the biochemical endonuclease assay, with IC50 values in the nM range. In the cell-based antiviral assay, a few analogs inhibited HCMV in low μM concentrations. Selected analogs were further characterized in a biophysical thermal shift assay (TSA) and in silico molecular docking, and the results support pUL89-C as the protein target of these inhibitors. Collectively, the biochemical, antiviral, biophysical, and in silico data reported herein indicate that the isomeric HtPD chemotypes 13-14 can serve as valuable chemical platforms for designing improved inhibitors of HCMV pUL89-C.
登录
查看更多内容
影响因子：
3.5
作者：
Chen, Yue-Lei;Zacharias, Jeana;Wang, Zhengqiang
通讯作者：
Wang, Zhengqiang
影响因子：
4.9
作者：
Huber, Andrew D.;Michailidis, Eleftherios;Sarafianos, Stefan G.
通讯作者：
Sarafianos, Stefan G.
影响因子：
3.7
作者：
Chen, Xiaoxi;Murawski, Anthony;Balimane, Praveen V.
通讯作者：
Balimane, Praveen V.
影响因子：
3.6
作者：
Ghorai, Jayanta;Anbarasan, Pazhamalai
通讯作者：
Anbarasan, Pazhamalai
影响因子：
3.5
作者：
Chen, Yue-Lei;Tang, Jing;Wang, Zhengqiang
通讯作者：
Wang, Zhengqiang