Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses.
Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses.
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DOI：
10.1016/j.antiviral.2018.08.012
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发表时间：
2018-10
影响因子：
7.6
通讯作者：
Basler CF
中科院分区：
文献类型：
--
作者：
Luthra P;Naidoo J;Pietzsch CA;De S;Khadka S;Anantpadma M;Williams CG;Edwards MR;Davey RA;Bukreyev A;Ready JM;Basler CF
可能用于治疗抑制埃博拉病毒（EBOV）和其他新出现病毒复制的特异性宿主途径仍未完全确定。对20万种化合物进行筛选，以抑制EBOV微小基因组（MG）测定，该测定测定了病毒聚合酶复合物的功能，并确定了几种具有氨基-四氢咔唑支架的化合物。该支架在结构上与GSK983相似，GSK983是一种先前被描述为具有广谱抗病毒活性的化合物，其通过抑制二氢羟酸脱氢酶（DHODH）来损害新生嘧啶的生物合成。我们合成了GSK983的外消旋版本化合物SW835，并证明SW835和另一种DHODH抑制剂brequinar在体外能有效抑制MG试验和EBOV、水疱性口炎病毒（VSV）和寨卡病毒（ZIKV）的复制。核苷和脱氧核苷补充研究表明，嘧啶池的消耗有助于这些化合物的抗病毒活性。与其他DHODH抑制剂一样，SW835和brequinar也能诱导干扰素刺激基因（ISGs）的表达。研究表明，ISG诱导不产生IFNα/β，独立于IFNα受体，不被ebov编码的IFN信号通路抑制因子阻断。此外，我们证明了转录因子IRF1是ISG诱导所必需的，并且IRF1的诱导需要DNA损伤反应激酶ATM。因此，从头开始的嘧啶生物合成对于EBOV和其他RNA病毒的复制至关重要，抑制这一途径会激活依赖于ATM和irf1的先天免疫反应，从而破坏EBOV的免疫逃避功能。
Specific host pathways that may be targeted therapeutically to inhibit the replication of Ebola virus (EBOV) and other emerging viruses remain incompletely defined. A screen of 200,000 compounds for inhibition of an EBOV minigenome (MG) assay that measures the function of the viral polymerase complex identified as hits several compounds with an amino-tetrahydrocarbazole scaffold. This scaffold was structurally similar to GSK983, a compound previously described as having broad-spectrum antiviral activity due to its impairing de novo pyrimidine biosynthesis through inhibition of dihydroorotate dehydrogenase (DHODH). We generated compound SW835, the racemic version of GSK983 and demonstrated that SW835 and brequinar, another DHODH inhibitor, potently inhibit the MG assay and the replication of EBOV, vesicular stomatitis virus (VSV) and Zika (ZIKV) in vitro. Nucleoside and deoxynucleoside supplementation studies demonstrated that depletion of pyrimidine pools contributes to antiviral activity of these compounds. As reported for other DHODH inhibitors, SW835 and brequinar also induced expression of interferon stimulated genes (ISGs). ISG induction was demonstrated to occur without production of IFNα/β and independently of the IFNα receptor and was not blocked by EBOV-encoded suppressors of IFN signaling pathways. Furthermore, we demonstrated that transcription factor IRF1 is required for this ISG induction, and that IRF1 induction requires the DNA damage response kinase ATM. Therefore, de novo pyrimidine biosynthesis is critical for the replication of EBOV and other RNA viruses and inhibition of this pathway activates an ATM and IRF1-dependent innate immune response that subverts EBOV immune evasion functions.
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影响因子：
6.7
作者：
Lubaki NM;Younan P;Santos RI;Meyer M;Iampietro M;Koup RA;Bukreyev A
通讯作者：
Bukreyev A
DOI：
10.1016/s0969-2126(00)00077-0
发表时间：
2000-01-15
期刊：
STRUCTURE WITH FOLDING & DESIGN
影响因子：
--
作者：
Liu, SP;Neidhardt, EA;Clardy, J
通讯作者：
Clardy, J
影响因子：
6.4
作者：
Feagins, Alicia R.;Basler, Christopher F.
通讯作者：
Basler, Christopher F.
DOI：
10.1073/pnas.220398297
发表时间：
2000-10-24
影响因子：
11.1
作者：
Basler, CF;Wang, XY;Palese, P
通讯作者：
Palese, P
影响因子：
5.4
作者：
Hartman, Amy L.;Bird, Brian H.;Nichol, Stuart T.
通讯作者：
Nichol, Stuart T.