8-Hydroxy-1,6-naphthyridine-7-carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease.
8-Hydroxy-1,6-naphthyridine-7-carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease.
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8-羟基-1,6-萘吡啶-7-羧酰胺作为人类巨细胞病毒PUL89核酸内切酶的抑制剂。
DOI：
10.1002/cmdc.202200334
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发表时间：
2022-09-05
期刊：
影响因子：
3.4
通讯作者：
Wang, Zhengqiang
中科院分区：
文献类型：
--
作者：
Jung, Eunkyung;Majima, Ryuichi;Edwards, Tiffany C.;Soto-Acosta, Ruben;Geraghty, Robert J.;Wang, Zhengqiang
人巨细胞病毒（HCMV）复制需要在pUL 89（pUL 89-C）的C末端的金属依赖性核酸内切酶，用于病毒基因组包装和切割。我们之前已经证明，pUL 89-C可以被设计的金属螯合化合物抑制。我们在此报告了一些8-羟基-1，6-萘啶亚型的合成，包括5-氯（亚型15），5-芳基（亚型16）和5-氨基（亚型17）变体。在生物化学内切核酸酶测定、生物物理热位移测定（TSA）、计算机分子对接中研究了类似物对pUL 89-C的抑制作用，并在基于细胞的测定中研究了其抗HCMV的抗病毒潜力。这些研究鉴定了8种8-羟基-1，6-萘啶-7-甲酰胺亚型的类似物以进行进一步表征，其中大多数以个位数μM IC 50值抑制pUL 89-C，并赋予μM范围内的抗病毒活性。所选类似物的TSA和分子建模证实了它们与pUL 89-C的结合。总的来说，我们的生物化学、抗病毒、生物物理和计算机数据表明，8-羟基-1，6-萘啶-7-甲酰胺亚型可用于设计HCMV pUL 89-C的抑制剂。 人巨细胞病毒（HCMV）的复制需要在pUL 89（pUL 89-C）的C末端的金属依赖性核酸内切酶，其在结构和催化上具有RNase H /整合酶样活性位点。我们在此报告了一些金属结合8-羟基-1，6-萘啶亚型的合成和生物化学、抗病毒、生物物理和计算机表征。合成的类似物在R1和R2处具有结构变化。
Human cytomegalovirus (HCMV) replication requires a metal‐dependent endonuclease at the C‐terminus of pUL89 (pUL89‐C) for viral genome packaging and cleavage. We have previously shown that pUL89‐C can be pharmacologically inhibited with designed metal‐chelating compounds. We report herein the synthesis of a few 8‐hydroxy‐1,6‐naphthyridine subtypes, including 5‐chloro (subtype 15), 5‐aryl (subtype 16), and 5‐amino (subtype 17) variants. Analogs were studied for the inhibition of pUL89‐C in a biochemical endonuclease assay, a biophysical thermal shift assay (TSA), in silico molecular docking, and for the antiviral potential against HCMV in cell‐based assays. These studies identified eight analogs of 8‐hydroxy‐1,6‐naphthyridine‐7‐carboxamide subtypes for further characterization, most of which inhibited pUL89‐C with single‐digit μM IC50 values, and conferred antiviral activity in μM range. TSA and molecular modeling of selected analogs corroborate their binding to pUL89‐C. Collectively, our biochemical, antiviral, biophysical and in silico data suggest that 8‐hydroxy‐1,6‐naphthyridine‐7‐carboxamide subtypes can be used for designing inhibitors of HCMV pUL89‐C. The replication of human cytomegalovirus (HCMV) requires a metal‐dependent endonuclease at the C‐terminus of pUL89 (pUL89‐C), which bears an RNase H / integrase‐like active site, structurally and catalytically. We report herein the synthesis and biochemical, antiviral, biophysical and in silico characterization of a few metal‐binding 8‐hydroxy‐1,6‐naphthyridine subtypes. Synthesized analogs feature structural variations at R1 and R2.
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