期刊
ANTIVIRAL RESEARCH
卷 217, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.antiviral.2023.105689
关键词
HCMV; CDK inhibitors; Abemaciclib; LDC4297; SAMHD1; pUL97
Human cytomegalovirus (HCMV) is a dangerous virus that causes serious infections in certain groups of people. It interacts with cellular kinases and encodes a viral kinase called pUL97, which phosphorylates an antiviral factor called SAMHD1. Researchers discovered that CDK inhibitors (CDKIs), drugs approved by the FDA, can inhibit the phosphorylation of SAMHD1 and effectively inhibit HCMV replication in macrophages. This study highlights the potential of CDKIs as antiviral drugs against HCMV and establishes SAMHD1 as a therapeutic target.
Human cytomegalovirus (HCMV) is a herpesvirus that causes life-threatening infections in newborns or immu-nosuppressed 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 macro-phages. 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.
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