Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA.
Department of Chemistry and Chemical-Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada.
Sci Rep. 2018 Nov 9;8(1):16662. doi: 10.1038/s41598-018-33904-y.
Acyclovir (ACV) is an effective antiviral agent for treating lytic Herpes Simplex virus, type 1 (HSV-1) infections, and it has dramatically reduced the mortality rate of herpes simplex encephalitis. However, HSV-1 resistance to ACV and its derivatives is being increasingly documented, particularly among immunocompromised individuals. The burgeoning drug resistance compels the search for a new generation of more efficacious anti-herpetic drugs. We have previously shown that trans-dihydrolycoricidine (R430), a lycorane-type alkaloid derivative, effectively inhibits HSV-1 infections in cultured cells. We now report that R430 also inhibits ACV-resistant HSV-1 strains, accompanied by global inhibition of viral gene transcription and enrichment of H3K27me3 methylation on viral gene promoters. Furthermore, we demonstrate that R430 prevents HSV-1 reactivation from latency in an ex vivo rodent model. Finally, among a panel of DNA viruses and RNA viruses, R430 inhibited Zika virus with high therapeutic index. Its therapeutic index is comparable to standard antiviral drugs, though it has greater toxicity in non-neuronal cells than in neuronal cells. Synthesis of additional derivatives could enable more efficacious antivirals and the identification of active pharmacophores.
阿昔洛韦（ACV）是一种有效的抗病毒药物，可用于治疗单纯疱疹病毒 1 型（HSV-1）的裂解感染，它显著降低了单纯疱疹性脑炎的死亡率。然而，HSV-1 对 ACV 及其衍生物的耐药性越来越多地被记录下来，特别是在免疫功能低下的个体中。不断增加的耐药性迫使人们寻找新一代更有效的抗疱疹药物。我们之前已经表明，trans-dihydrolycoricidine（R430），一种石蒜碱型生物碱衍生物，有效地抑制培养细胞中的 HSV-1 感染。我们现在报告 R430 还抑制 ACV 耐药的 HSV-1 株，同时伴有病毒基因转录的全局抑制和病毒基因启动子上 H3K27me3 甲基化的富集。此外，我们证明 R430 可防止 HSV-1 在体外啮齿动物模型中从潜伏状态重新激活。最后，在一组 DNA 病毒和 RNA 病毒中，R430 对寨卡病毒具有高治疗指数。它的治疗指数与标准抗病毒药物相当，尽管它在非神经元细胞中的毒性比在神经元细胞中更大。更多衍生物的合成可以实现更有效的抗病毒药物，并确定有效的药效团。
