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Abemaciclib restricts HCMV replication by suppressing pUL97-mediated phosphorylation of SAMHD1.
- Source :
-
Antiviral research [Antiviral Res] 2023 Sep; Vol. 217, pp. 105689. Date of Electronic Publication: 2023 Jul 27. - Publication Year :
- 2023
-
Abstract
- 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2023 Elsevier B.V. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1872-9096
- Volume :
- 217
- Database :
- MEDLINE
- Journal :
- Antiviral research
- Publication Type :
- Academic Journal
- Accession number :
- 37516154
- Full Text :
- https://doi.org/10.1016/j.antiviral.2023.105689