Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.
Laboratory of Molecular Pediatrics, Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Antiviral Res. 2023 Sep;217:105689. doi: 10.1016/j.antiviral.2023.105689. Epub 2023 Jul 27.
Human cytomegalovirus (HCMV) is a herpesvirus that causes life-threatening infections in newborns or immunosuppressed patients. For viral replication, HCMV establishes a network of cellular interactions, among others cyclin-dependent kinases (CDK). Furthermore, HCMV encodes pUL97, a viral kinase, which is a CDK-homologue. HCMV uses pUL97 in order to phosphorylate and thereby antagonize SAMHD1, an antiviral host cell factor. Since HCMV has several mechanisms to evade restriction by SAMHD1, we first analyzed the kinetics of SAMHD1-inactivation and found that phosphorylation of SAMHD1 by pUL97 occurs directly after infection of macrophages. We hence hypothesized that inhibition of this process qualifies as efficient antiviral target and FDA approved CDK-inhibitors (CDKIs) might be potent antivirals that prevent the inactivation of SAMHD1. Indeed, Abemaciclib, a 2nd generation CDKI exhibited superior IC50s against HCMV in infected macrophages and the antiviral activity largely relied on its ability to block pUL97-mediated SAMHD1-phosphorylation. Altogether, our study highlights the therapeutic potential of clinically-approved CDKIs as antivirals against HCMV, sheds light on their mode of action and establishes SAMHD1 as a valid and highly potent therapeutic target.
人巨细胞病毒（HCMV）是一种疱疹病毒，可导致新生儿或免疫抑制患者发生危及生命的感染。为了进行病毒复制，HCMV 建立了细胞相互作用网络，其中包括细胞周期蛋白依赖性激酶（CDK）。此外，HCMV 编码了一种病毒激酶 pUL97，它是 CDK 的同源物。HCMV 利用 pUL97 对抗病毒宿主细胞因子 SAMHD1 进行磷酸化，从而拮抗 SAMHD1。由于 HCMV 有几种逃避 SAMHD1 限制的机制，我们首先分析了 SAMHD1 失活的动力学，发现 pUL97 对 SAMHD1 的磷酸化发生在巨噬细胞感染后直接进行。因此，我们假设抑制这一过程可作为有效的抗病毒靶点，而已获 FDA 批准的 CDK 抑制剂（CDKIs）可能是有效的抗病毒药物，可防止 SAMHD1 的失活。事实上，第二代 CDKIs 中的 Abemaciclib 在感染的巨噬细胞中对 HCMV 具有优越的 IC50，其抗病毒活性主要依赖于其阻断 pUL97 介导的 SAMHD1 磷酸化的能力。总的来说，我们的研究强调了临床批准的 CDKIs 作为抗 HCMV 病毒药物的治疗潜力，阐明了它们的作用模式，并确立了 SAMHD1 作为一种有效且强效的治疗靶点。
