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Article

Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity

1
Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
2
Serology and Virology Division, NSW Health Pathology Microbiology, Prince of Wales Hospital, Schools of Women’s and Children’s Health, Medicine and Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2031, Australia
3
Institute of Organic Chemistry I, FAU, 91058 Erlangen, Germany
4
Institute of Virology, Freie Universität Berlin, 14163 Berlin, Germany
*
Authors to whom correspondence should be addressed.
Academic Editor: Raffaele Bruno
Int. J. Mol. Sci. 2021, 22(23), 12858; https://doi.org/10.3390/ijms222312858
Received: 20 October 2021 / Revised: 24 November 2021 / Accepted: 24 November 2021 / Published: 27 November 2021
(This article belongs to the Section Macromolecules)
Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development. View Full-Text
Keywords: human cytomegalovirus; human/animal pathogenic viruses; antiviral drugs; direct-acting antivirals; host-directed antivirals; PROteolysis TArgeting Chimeras; PROTAC-based targeting strategy; new drug qualities human cytomegalovirus; human/animal pathogenic viruses; antiviral drugs; direct-acting antivirals; host-directed antivirals; PROteolysis TArgeting Chimeras; PROTAC-based targeting strategy; new drug qualities
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MDPI and ACS Style

Hahn, F.; Hamilton, S.T.; Wangen, C.; Wild, M.; Kicuntod, J.; Brückner, N.; Follett, J.E.L.; Herrmann, L.; Kheimar, A.; Kaufer, B.B.; Rawlinson, W.D.; Tsogoeva, S.B.; Marschall, M. Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity. Int. J. Mol. Sci. 2021, 22, 12858. https://doi.org/10.3390/ijms222312858

AMA Style

Hahn F, Hamilton ST, Wangen C, Wild M, Kicuntod J, Brückner N, Follett JEL, Herrmann L, Kheimar A, Kaufer BB, Rawlinson WD, Tsogoeva SB, Marschall M. Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity. International Journal of Molecular Sciences. 2021; 22(23):12858. https://doi.org/10.3390/ijms222312858

Chicago/Turabian Style

Hahn, Friedrich, Stuart T. Hamilton, Christina Wangen, Markus Wild, Jintawee Kicuntod, Nadine Brückner, Jasmine E.L. Follett, Lars Herrmann, Ahmed Kheimar, Benedikt B. Kaufer, William D. Rawlinson, Svetlana B. Tsogoeva, and Manfred Marschall. 2021. "Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity" International Journal of Molecular Sciences 22, no. 23: 12858. https://doi.org/10.3390/ijms222312858

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