O-2-Alkylated Cytosine Acyclic Nucleoside Phosphonamidate Prodrugs Display Pan-Genotype Antiviral Activity against African Swine Fever Virus.
O-2-Alkylated Cytosine Acyclic Nucleoside Phosphonamidate Prodrugs Display Pan-Genotype Antiviral Activity against African Swine Fever Virus.
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非洲猪瘟病毒（ASFV）是一种高度传染性的出血性疾病，在家猪中的病死率接近100%。ASFV造成了巨大的经济损失，但尽管不断努力，目前还没有疫苗或抗病毒剂。控制ASFV传播的努力取决于早期检测、遵守生物安全措施和扑杀受感染的牛群。然而，一种有效的抗病毒剂可以代替疫苗或与疫苗结合使用，以有效地遏制ASFV的爆发。测定了O-2-烷基化3-氟-2-（膦酰甲氧基）丙基胞嘧啶[（R）-O-2-烷基化FPMPC]的两种酰胺化前药（化合物1a和1b）对4种不同基因型ASFV分离株的剂量依赖性抗病毒活性。在原代猪巨噬细胞中，发现两种化合物在非细胞毒性浓度（<25 μM）下抑制ASFV子代病毒输出>90%。病毒转录和病毒蛋白质合成的分析表明，这些无环核苷酸类似物抑制晚期基因表达。有趣的是，添加时间研究表明化合物的不同病毒靶点，这可能归因于其不同的氨基酸前药部分。鉴于其有前途的抗病毒活性，这些核苷酸类似物值得进一步评价作为潜在的预防和/或治疗剂对ASFV感染和其体内抗病毒疗效应被考虑。非洲猪瘟病毒是一种高度传染性的出血性病毒性疾病。自2007年跨大陆传播到格鲁吉亚以来，ASFV继续在地球仪上传播到以前没有感染的国家。它造成了国内猪群的大量损失，并对全球养猪业构成了重大威胁。尽管不断努力，但目前没有可用的疫苗;在没有疫苗的情况下，抗病毒剂可能是一种可行的替代品。我们的研究的意义在于鉴定O-2-烷基化3-氟-2-（膦酰甲氧基）丙基胞嘧啶前药的泛基因型抗病毒活性，这将推动这些化合物作为抗ASFV的抗病毒药物的进一步研究。
African swine fever virus (ASFV) causes a highly contagious hemorrhagic disease with case fatality rates approaching 100% in domestic pigs. ASFV is responsible for substantial economic losses, but despite ongoing efforts, no vaccine or antiviral agent is currently available. Attempts to control the spread of ASFV are dependent on early detection, adherence to biosecurity measures, and culling of infected herds. However, an effective antiviral agent may be used in lieu of or in conjunction with a vaccine to effectively curb ASFV outbreaks. The dose-dependent antiviral activities of two amidate prodrugs (compounds 1a and 1b) of O-2-alkylated 3-fluoro-2-(phosphonomethoxy)propyl cytosine [(R)-O-2-alkylated FPMPC] against ASFV isolates of four different genotypes were determined. Both compounds were found to inhibit ASFV progeny virus output by >90% at noncytotoxic concentrations (<25 μM) in primary porcine macrophages. Analysis of viral transcription and viral protein synthesis indicated that these acyclic nucleotide analogues inhibited late gene expression. Interestingly, time-of-addition studies suggest different viral targets of the compounds, which may be attributed to their differing amino acid prodrug moieties. In view of their promising antiviral activity, these nucleotide analogues merit further evaluation as potential prophylactic and/or therapeutic agents against ASFV infection and their antiviral efficacy in vivo should be considered. IMPORTANCE African swine fever virus is a highly contagious hemorrhagic viral disease. Since its transcontinental spread to Georgia in 2007, ASFV has continued to spread across the globe into countries previously without infection. It is responsible for substantial losses in the domestic pig population and presents a significant threat to the global swine industry. Despite ongoing efforts, there are no vaccines currently available; in their absence, antiviral agents may be a viable alternative. The significance of our research is in identifying the pan-genotype antiviral activity of prodrugs of O-2-alkylated 3-fluoro-2-(phosphonomethoxy)propyl cytosine, which will drive further research on the development of these compounds as antivirals against ASFV.
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DOI：
10.1016/0006-291x(88)90644-4
发表时间：
1988-07-15
影响因子：
3.1
作者：
ARZUZA, O;GARCIAVILLALON, D;DECLERCQ, E
通讯作者：
DECLERCQ, E
影响因子：
2.7
作者：
Hakobyan, Astghik;Arabyan, Erik;Zakaryan, Hovakim
通讯作者：
Zakaryan, Hovakim
影响因子：
5.4
作者：
Cackett G;Portugal R;Matelska D;Dixon L;Werner F
通讯作者：
Werner F
影响因子：
4.2
作者：
Luo, Min;Groaz, Elisabetta;Herdewijn, Piet
通讯作者：
Herdewijn, Piet
影响因子：
7.6
作者：
Freitas, Ferdinando B.;Frouco, Goncalo;Ferreira, Fernando
通讯作者：
Ferreira, Fernando