Human cytomegalovirus (HCMV) causes serious and even life-threatening diseases, particularly upon congenital or post-transplant infection. Treatment of HCMV infections with currently available drugs targeting viral enzymes is often limited by severe side effects and the emergence of drug-resistant viruses. To avoid this problem, novel therapeutic options directed to host proteins involved in virus replication are being investigated. Recently, we described the pronounced antiherpesviral activity of the trimeric artesunate derivative TF27 at low nanomolar concentrations in vitro and in vivo. In the present study, we report first data on the prophylactic efficacy of TF27 against human and murine CMV and the oncogenic avian alphaherpesvirus Marek's disease virus (MDV). The main findings of this study are (i) a pronounced activity of the experimental drug TF27 against alpha- and betaherpesviruses in vitro upon prophylactic treatment and (ii) a therapeutic and prophylactic efficacy upon oral treatment in an immunocompetent mouse model. Moreover, our data highlight (iii) the tolerability of orally administered TF27 free of compound-associated adverse events and further confirm (iv) the suitability of cellular factors as primary antiviral targets. Thus, we provide evidence for therapeutic and prophylactic antiherpesviral efficacy of TF27 upon oral treatment in immunocompetent hosts and thereby underline its potential for future antiviral drug development.

中文翻译：

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青蒿琥酯三聚体衍生物TF27具有很强的抗巨细胞病毒作用：专注于免疫功能小鼠的预防作用和口服治疗。

人类巨细胞病毒（HCMV）会导致严重甚至威胁生命的疾病，尤其是在先天性或移植后感染时。用目前可用的靶向病毒酶的药物治疗HCMV感染通常受到严重的副作用和耐药病毒的出现的限制。为了避免这个问题，正在研究针对涉及病毒复制的宿主蛋白的新颖治疗选择。最近，我们描述了三聚体青蒿琥酯衍生物TF27在体外和体内低纳摩尔浓度下的明显抗疱疹病毒活性。在本研究中，我们报告了TF27对人和鼠CMV和致癌性禽α疱疹病毒马立克氏病病毒（MDV）的预防功效的第一份数据。这项研究的主要发现是（i）预防性治疗后，实验药物TF27在体外具有明显的针对α和β疱疹病毒的活性，以及​​（ii）口服免疫治疗小鼠模型中的治疗和预防功效。此外，我们的数据突出了（iii）口服给予TF27且无化合物相关不良事件的耐受性，并进一步证实（iv）细胞因子作为主要抗病毒靶标的适用性。因此，我们提供了在有免疫能力的宿主中口服治疗后TF27的治疗性和预防性抗疱疹病毒功效的证据，从而突显了其未来抗病毒药物开发的潜力。