Mechanisms of anti-vesicular stomatitis virus activity of deazaneplanocin and its 3-brominated analogs.
Mechanisms of anti-vesicular stomatitis virus activity of deazaneplanocin and its 3-brominated analogs.
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DOI：
10.1016/j.antiviral.2021.105088
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发表时间：
2021-07
影响因子：
7.6
通讯作者：
Basler CF
中科院分区：
文献类型：
--
作者：
Gibbons JS;Khadka S;Williams CG;Wang L;Schneller SW;Liu C;Tufariello JM;Basler CF
3-去氮Planocin A（DzNep）及其3-溴化类似物抑制几种RNA病毒的复制。这种抗病毒活性归因于S-腺苷高半胱氨酸水解酶（SAHase）的抑制，从而抑制病毒甲基转移酶，损害病毒转录物的翻译。一些衍生物的L-对映体保留抗病毒活性，尽管在体外显着降低SAHase的抑制。为了更好地理解这些化合物发挥其抗病毒作用的机制，我们比较了DzNep，其3-溴代衍生物CL 123和相关的对映体CL 4033和CL 4053对模型负义RNA病毒水泡性口炎病毒（VSV）的活性。在细胞培养中，DzNep、CL 123和CL 4033各自表现出纳摩尔范围内的50%抑制浓度（IC 50），而L型CL 4053的IC 50高34-85倍。当选择CL 123抗性突变体（VSVR）时，它对每种奈普霉素类似物都表现出交叉抗性，但对腺苷类似物BCX 4430（RNA链终止剂）保持敏感性。VSVR测序鉴定了病毒大（L）蛋白C-末端结构域（CTD）中的突变，该结构域涉及L蛋白甲基转移酶活性的调节。CL 123抑制VSV病毒mRNA 5'帽甲基化，损害病毒蛋白质合成并减少病毒mRNA与多核糖体的结合。还证实了对病毒转录的适度影响。在这些试验中，VSVR均表现出部分抗性，但在不存在抑制剂的情况下，相对于亲本VSV，其复制受损。这些数据表明，DzNep、CL 123和CL 4033通过损害病毒mRNA帽甲基化来抑制VSV，并且基于VSVR的交叉抗性的L型CL 4053可能通过类似的机制起作用。
3-deazaneplanocin A (DzNep) and its 3-brominated analogues inhibit replication of several RNA viruses. This antiviral activity is attributed to inhibition of S-adenosyl homocysteine hydrolase (SAHase) and consequently inhibition of viral methyltransferases, impairing translation of viral transcripts. The L-enantiomers of some derivatives retain antiviral activity despite dramatically reduced inhibition of SAHase in vitro. To better understand the mechanisms by which these compounds exert their antiviral effects, we compared DzNep, its 3-bromo-derivative, CL123, and the related enantiomers, CL4033 and CL4053, for their activities towards the model negative-sense RNA virus vesicular stomatitis virus (VSV). In cell culture, DzNep, CL123 and CL4033 each exhibited 50 percent inhibitory concentrations (IC50s) in the nanomolar range whereas the IC50 for the L-form, CL4053, was 34-85 times higher. When a CL123-resistant mutant (VSVR) was selected, it exhibited cross-resistance to each of the neplanocin analogs, but retained sensitivity to the adenosine analog BCX4430, an RNA chain terminator. Sequencing of VSVR identified a mutation in the C-terminal domain (CTD) of the viral large (L) protein, a domain implicated in regulation of L protein methyltransferase activity. CL123 inhibited VSV viral mRNA 5’ cap methylation, impaired viral protein synthesis and decreased association of viral mRNAs with polysomes. Modest impacts on viral transcription were also demonstrated. VSVR exhibited partial resistance in each of these assays but its replication was impaired, relative to the parent VSV, in the absence of the inhibitors. These data suggest that DzNep, CL123 and CL4033 inhibit VSV through impairment of viral mRNA cap methylation and that the L-form, CL4053, based on the cross-resistance of VSVR, may act by a similar mechanism.
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DOI：
10.1038/nrmicro975
发表时间：
2004-09
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
De Clercq E
通讯作者：
De Clercq E
影响因子：
5.4
作者：
Li, Jianrong;Rahmeh, Amal;Whelan, Sean P. J.
通讯作者：
Whelan, Sean P. J.
影响因子：
4.5
作者：
Beilharz, Traude H.;Preiss, Thomas
通讯作者：
Preiss, Thomas
影响因子：
3.7
作者：
Grdzelishvili, Valery Z.;Smallwood, Sherin;Moyer, Sue A.
通讯作者：
Moyer, Sue A.
DOI：
10.1073/pnas.73.5.1504
发表时间：
1976-01-01
影响因子：
11.1
作者：
ABRAHAM, G;BANERJEE, AK
通讯作者：
BANERJEE, AK