Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cells and Viruses
2.2. Antiviral Compounds
2.3. Animal Experimentation
2.4. Mouse Organ Homogenization and Plaque Reduction Assay on MEFs
2.5. Drug Interaction Assessment via Loewe Additivity Fixed-Dose Assay Adapted to HCMV-GFP In Vitro Infection
2.6. Drug Interaction Assessment via Loewe Additivity Fixed-Dose Assay Adapted to Non-Human GFP-Expressing Reporter CMVs In Vitro Infection
2.7. Drug Interaction Assessment via Loewe Additivity Fixed-Dose Assay Adapted to Plaque Reduction Read-Out of Non-Human CMVs
2.8. Quantitation of pUL69 Shuttling Activity via Heterokaryon Assay
2.9. Measurement of Viral Polymerase Activity Utilizing DNA Labeling by Click Fluorescence-Conjugation
3. Results
3.1. Assessment of In Vitro Synergistic Anti-HCMV Interaction between vCDK and CDK Inhibitors
3.2. Specific Synergism between the vCDK/pUL97 Inhibitor MBV and the CDK7 Inhibitor LDC4297 in Non-Human Cytomegalovirus Replication Models
3.3. Extension of the Synergy Approach In Vivo Using the Recombinant MCMV-UL97/Mouse Model
3.4. Mechanistic Aspects of the Antiviral MBV + LDC4297 Synergistic Drug Activity
3.5. Absence of Viral Resistance Formation upon MBV + LDC4297 Synergistic Drug Treatment in Long-Term Settings
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Cannon, M.J.; Schmid, D.S.; Hyde, T.B. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev. Med. Virol. 2010, 20, 202–213. [Google Scholar] [CrossRef] [PubMed]
- Griffiths, P.; Reeves, M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat. Rev. Microbiol. 2021, 19, 759–773. [Google Scholar] [CrossRef] [PubMed]
- Tsutsui, Y. Effects of cytomegalovirus infection on embryogenesis and brain development. Congenit. Anom. 2009, 49, 47–55. [Google Scholar] [CrossRef] [PubMed]
- Buxmann, H.; Hamprecht, K.; Meyer-Wittkopf, M.; Friese, K. Primary Human Cytomegalovirus (HCMV) Infection in Pregnancy. Dtsch. Arztebl. Int. 2017, 114, 45–52. [Google Scholar] [CrossRef] [PubMed]
- Majewska, A.; Mlynarczyk-Bonikowska, B. 40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs? Int. J. Mol. Sci. 2022, 23, 3431. [Google Scholar] [CrossRef] [PubMed]
- Piret, J.; Boivin, G. Clinical development of letermovir and maribavir: Overview of human cytomegalovirus drug resistance. Antivir. Res. 2019, 163, 91–105. [Google Scholar] [CrossRef] [PubMed]
- Chen, S.-J.; Wang, S.-C.; Chen, Y.-C. Challenges, Recent Advances and Perspectives in the Treatment of Human Cytomegalovirus Infections. Trop. Med. Infect. Dis. 2022, 7, 439. [Google Scholar] [CrossRef] [PubMed]
- Gugliesi, F.; Coscia, A.; Griffante, G.; Galitska, G.; Pasquero, S.; Albano, C.; Biolatti, M. Where do we Stand after Decades of Studying Human Cytomegalovirus? Microorganisms 2020, 8, 685. [Google Scholar] [CrossRef]
- Bogner, E.; Egorova, A.; Makarov, V. Small Molecules—Prospective Novel HCMV Inhibitors. Viruses 2021, 13, 474. [Google Scholar] [CrossRef]
- Bachman, L.O.; Zwezdaryk, K.J. Targeting the Host Mitochondria as a Novel Human Cytomegalovirus Antiviral Strategy. Viruses 2023, 15, 1083. [Google Scholar] [CrossRef]
- Krishna, B.A.; Wills, M.R.; Sinclair, J.H. Advances in the treatment of cytomegalovirus. Br. Med. Bull. 2019, 131, 5–17. [Google Scholar] [CrossRef] [PubMed]
- Wild, M.; Hahn, F.; Brückner, N.; Schütz, M.; Wangen, C.; Wagner, S.; Sommerer, M.; Strobl, S.; Marschall, M. Cyclin-Dependent Kinases (CDKs) and the Human Cytomegalovirus-Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations. Int. J. Mol. Sci. 2022, 23, 2493. [Google Scholar] [CrossRef] [PubMed]
- Wild, M.; Kicuntod, J.; Seyler, L.; Wangen, C.; Bertzbach, L.D.; Conradie, A.M.; Kaufer, B.B.; Wagner, S.; Michel, D.; Eickhoff, J.; et al. Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs). Int. J. Mol. Sci. 2021, 22, 575. [Google Scholar] [CrossRef] [PubMed]
- Hahn, F.; Hamilton, S.T.; Wangen, C.; Wild, M.; Kicuntod, J.; Brückner, N.; Follett, J.E.L.; Herrmann, L.; Kheimar, A.; Kaufer, B.B.; et al. Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity. Int. J. Mol. Sci. 2021, 22, 12858. [Google Scholar] [CrossRef] [PubMed]
- Syrigos, G.V.; Feige, M.; Dirlam, A.; Businger, R.; Gruska, I.; Wiebusch, L.; Hamprecht, K.; Schindler, M. Abemaciclib restricts HCMV replication by suppressing pUL97-mediated phosphorylation of SAMHD1. bioRxiv 2023. bioRxiv:10.1101/2023.02.01.526617. [Google Scholar] [CrossRef]
- Hutterer, C.; Eickhoff, J.; Milbradt, J.; Korn, K.; Zeitträger, I.; Bahsi, H.; Wagner, S.; Zischinsky, G.; Wolf, A.; Degenhart, C.; et al. A novel CDK7 inhibitor of the Pyrazolotriazine class exerts broad-spectrum antiviral activity at nanomolar concentrations. Antimicrob. Agents Chemother. 2015, 59, 2062–2071. [Google Scholar] [CrossRef]
- Steingruber, M.; Marschall, M. The Cytomegalovirus Protein Kinase pUL97:Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting. Microorganisms 2020, 8, 515. [Google Scholar] [CrossRef]
- Halpern-Cohen, V.; Blumberg, E.A. New Perspectives on Antimicrobial Agents: Maribavir. Antimicrob. Agents Chemother. 2022, 66, e02405-21. [Google Scholar] [CrossRef]
- Schütz, M.; Müller, R.; Socher, E.; Wangen, C.; Full, F.; Wyler, E.; Wong, D.; Scherer, M.; Stamminger, T.; Chou, S.; et al. Highly Conserved Interaction Profiles between Clinically Relevant Mutants of the Cytomegalovirus CDK-like Kinase pUL97 and Human Cyclins: Functional Significance of Cyclin H. Int. J. Mol. Sci. 2022, 23, 11814. [Google Scholar] [CrossRef]
- Schütz, M.; Wangen, C.; Sommerer, M.; Kögler, M.; Eickhoff, J.; Degenhart, C.; Klebl, B.; Naing, Z.; Egilmezer, E.; Hamilton, S.T.; et al. Cytomegalovirus cyclin-dependent kinase ortholog vCDK/pUL97 undergoes regulatory interaction with human cyclin H and CDK7 to codetermine viral replication efficiency. Virus Res. 2023, 335, 199200. [Google Scholar] [CrossRef]
- Steingruber, M.; Keller, L.; Socher, E.; Ferre, S.; Hesse, A.M.; Couté, Y.; Hahn, F.; Büscher, N.; Plachter, B.; Sticht, H.; et al. Cyclins B1, T1, and H differ in their molecular mode of interaction with cytomegalovirus protein kinase pUL97. J. Biol. Chem. 2019, 294, 6188–6203. [Google Scholar] [CrossRef]
- McGregor, A.; Schleiss, M.R. Molecular cloning of the guinea pig cytomegalovirus (GPCMV) genome as an infectious bacterial artificial chromosome (BAC) in Escherichia coli. Mol. Genet. Metab. 2001, 72, 15–26. [Google Scholar] [CrossRef] [PubMed]
- Marschall, M.; Freitag, M.; Weiler, S.; Sorg, G.; Stamminger, T. Recombinant green fluorescent protein-expressing human cytomegalovirus as a tool for screening antiviral agents. Antimicrob. Agents Chemother. 2000, 44, 1588–1597. [Google Scholar] [CrossRef] [PubMed]
- Wagner, M.; Michel, D.; Schaarschmidt, P.; Vaida, B.; Jonjic, S.; Messerle, M.; Mertens, T.; Koszinowski, U. Comparison between human cytomegalovirus pUL97 and murine cytomegalovirus (MCMV) pM97 expressed by MCMV and vaccinia virus: pM97 does not confer ganciclovir sensitivity. J. Virol. 2000, 74, 10729–10736. [Google Scholar] [CrossRef] [PubMed]
- Chang, W.L.; Tarantal, A.F.; Zhou, S.S.; Borowsky, A.D.; Barry, P.A. A recombinant rhesus cytomegalovirus expressing enhanced green fluorescent protein retains the wild-type phenotype and pathogenicity in fetal macaques. J. Virol. 2002, 76, 9493–9504. [Google Scholar] [CrossRef] [PubMed]
- Chou, T.; Martin, N. CompuSyn for Drug Combinations: PC Software and User’s Guide: A Computer Program for Quantitation of Synergism and Antagonism in Drug Combinations, and the Determination of IC50 and ED50 and LD50 Values; ComboSyn: Paramus, NJ, USA, 2005. [Google Scholar]
- Lischka, P.; Rosorius, O.; Trommer, E.; Stamminger, T. A novel transferable nuclear export signal mediates CRM1-independent nucleocytoplasmic shuttling of the human cytomegalovirus transactivator protein pUL69. Embo J. 2001, 20, 7271–7283. [Google Scholar] [CrossRef] [PubMed]
- Schindelin, J.; Arganda-Carreras, I.; Frise, E.; Kaynig, V.; Longair, M.; Pietzsch, T.; Preibisch, S.; Rueden, C.; Saalfeld, S.; Schmid, B.; et al. Fiji: An open-source platform for biological-image analysis. Nat. Methods 2012, 9, 676–682. [Google Scholar] [CrossRef]
- Kicuntod, J.; Häge, S.; Hahn, F.; Sticht, H.; Marschall, M. The Oligomeric Assemblies of Cytomegalovirus Core Nuclear Egress Proteins Are Associated with Host Kinases and Show Sensitivity to Antiviral Kinase Inhibitors. Viruses 2022, 14, 1021. [Google Scholar] [CrossRef]
- Hahn, F.; Häge, S.; Herrmann, A.; Wangen, C.; Kicuntod, J.; Jungnickl, D.; Tillmanns, J.; Müller, R.; Fraedrich, K.; Überla, K.; et al. Methodological Development of a Multi-Readout Assay for the Assessment of Antiviral Drugs against SARS-CoV-2. Pathogens 2021, 10, 1076. [Google Scholar] [CrossRef]
- Sonntag, E.; Hahn, F.; Bertzbach, L.D.; Seyler, L.; Wangen, C.; Müller, R.; Tannig, P.; Grau, B.; Baumann, M.; Zent, E.; et al. In vivo proof-of-concept for two experimental antiviral drugs, both directed to cellular targets, using a murine cytomegalovirus model. Antivir. Res. 2019, 161, 63–69. [Google Scholar] [CrossRef]
- Hutterer, C.; Hamilton, S.; Steingruber, M.; Zeitträger, I.; Bahsi, H.; Thuma, N.; Naing, Z.; Örfi, Z.; Örfi, L.; Socher, E.; et al. The chemical class of quinazoline compounds provides a core structure for the design of anticytomegaloviral kinase inhibitors. Antivir. Res. 2016, 134, 130–143. [Google Scholar] [CrossRef] [PubMed]
- Graf, L.; Feichtinger, S.; Naing, Z.; Hutterer, C.; Milbradt, J.; Webel, R.; Wagner, S.; Scott, G.M.; Hamilton, S.T.; Rawlinson, W.D.; et al. New insight into the phosphorylation-regulated intranuclear localization of human cytomegalovirus pUL69 mediated by cyclin-dependent kinases (CDKs) and viral CDK orthologue pUL97. J. Gen. Virol. 2016, 97, 144–151. [Google Scholar] [CrossRef] [PubMed]
- Feichtinger, S.; Stamminger, T.; Müller, R.; Graf, L.; Klebl, B.; Eickhoff, J.; Marschall, M. Recruitment of cyclin-dependent kinase 9 to nuclear compartments during cytomegalovirus late replication: Importance of an interaction between viral pUL69 and cyclin T1. J. Gen. Virol. 2011, 92, 1519–1531. [Google Scholar] [CrossRef] [PubMed]
- Rechter, S.; Scott, G.M.; Eickhoff, J.; Zielke, K.; Auerochs, S.; Müller, R.; Stamminger, T.; Rawlinson, W.D.; Marschall, M. Cyclin-dependent Kinases Phosphorylate the Cytomegalovirus RNA Export Protein pUL69 and Modulate Its Nuclear Localization and Activity. J. Biol. Chem. 2009, 284, 8605–8613. [Google Scholar] [CrossRef] [PubMed]
- Sinzger, C.; Digel, M.; Jahn, G. Cytomegalovirus cell tropism. Curr. Top. Microbiol. Immunol. 2008, 325, 63–83. [Google Scholar] [CrossRef] [PubMed]
- Thomas, M.; Rechter, S.; Milbradt, J.; Auerochs, S.; Müller, R.; Stamminger, T.; Marschall, M. Cytomegaloviral protein kinase pUL97 interacts with the nuclear mRNA export factor pUL69 to modulate its intranuclear localization and activity. J. Gen. Virol. 2009, 90, 567–578. [Google Scholar] [CrossRef] [PubMed]
- Schütz, M.; Thomas, M.; Wangen, C.; Wagner, S.; Rauschert, L.; Errerd, T.; Kießling, M.; Sticht, H.; Milbradt, J.; Marschall, M. The peptidyl-prolyl cis/trans isomerase Pin1 interacts with three early regulatory proteins of human cytomegalovirus. Virus Res. 2020, 285, 198023. [Google Scholar] [CrossRef]
- Shyr, Z.A.; Cheng, Y.-S.; Lo, D.C.; Zheng, W. Drug combination therapy for emerging viral diseases. Drug. Discov. Today 2021, 26, 2367–2376. [Google Scholar] [CrossRef]
- Evers, D.L.; Komazin, G.; Shin, D.; Hwang, D.D.; Townsend, L.B.; Drach, J.C. Interactions among antiviral drugs acting late in the replication cycle of human cytomegalovirus. Antiviral Res 2002, 56, 61–72. [Google Scholar] [CrossRef]
- Azad, R.F.; Brown-Driver, V.; Buckheit, R.W., Jr.; Anderson, K.P. Antiviral activity of a phosphorothioate oligonucleotide complementary to human cytomegalovirus RNA when used in combination with antiviral nucleoside analogs. Antivir. Res. 1995, 28, 101–111. [Google Scholar] [CrossRef]
- Chou, S.; Ercolani, R.J.; Derakhchan, K. Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus. Antivir. Res. 2018, 157, 128–133. [Google Scholar] [CrossRef] [PubMed]
- Oiknine-Djian, E.; Bar-On, S.; Laskov, I.; Lantsberg, D.; Haynes, R.K.; Panet, A.; Wolf, D.G. Artemisone demonstrates synergistic antiviral activity in combination with approved and experimental drugs active against human cytomegalovirus. Antivir. Res. 2019, 172, 104639. [Google Scholar] [CrossRef] [PubMed]
- Bhave, S.; Elford, H.; McVoy, M.A. Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir. Antivir. Res. 2013, 100, 151–158. [Google Scholar] [CrossRef] [PubMed]
- Wildum, S.; Zimmermann, H.; Lischka, P. In Vitro Drug Combination Studies of Letermovir (AIC246, MK-8228) with Approved Anti-Human Cytomegalovirus (HCMV) and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication. Antimicrob. Agents Chemother. 2015, 59, 3140–3148. [Google Scholar] [CrossRef] [PubMed]
- Panda, K.; Parashar, D.; Viswanathan, R. An Update on Current Antiviral Strategies to Combat Human Cytomegalovirus Infection. Viruses 2023, 15, 1358. [Google Scholar] [CrossRef] [PubMed]
- Shiraki, K.; Yasumoto, S.; Toyama, N.; Fukuda, H. Amenamevir, a Helicase-Primase Inhibitor, for the Optimal Treatment of Herpes Zoster. Viruses 2021, 13, 1547. [Google Scholar] [CrossRef] [PubMed]
- Biswas, S.; Sukla, S.; Field, H.J. Helicase-primase inhibitors for herpes simplex virus: Looking to the future of non-nucleoside inhibitors for treating herpes virus infections. Future Med. Chem. 2014, 6, 45–55. [Google Scholar] [CrossRef]
- Birkmann, A.; Bonsmann, S.; Kropeit, D.; Pfaff, T.; Rangaraju, M.; Sumner, M.; Timmler, B.; Zimmermann, H.; Buschmann, H.; Ruebsamen-Schaeff, H. Discovery, Chemistry, and Preclinical Development of Pritelivir, a Novel Treatment Option for Acyclovir-Resistant Herpes Simplex Virus Infections. J. Med. Chem. 2022, 65, 13614–13628. [Google Scholar] [CrossRef]
- Tillmanns, J.; Häge, S.; Borst, E.M.; Wardin, J.; Eickhoff, J.; Klebl, B.; Wagner, S.; Wangen, C.; Hahn, F.; Socher, E.; et al. Assessment of Covalently Binding Warhead Compounds in the Validation of the Cytomegalovirus Nuclear Egress Complex as an Antiviral Target. Cells 2023, 12, 1162. [Google Scholar] [CrossRef]
- Kicuntod, J.; Häge, S.; Lösing, J.; Kopar, S.; Muller, Y.A.; Marschall, M. An antiviral targeting strategy based on the inducible interference with cytomegalovirus nuclear egress complex. Antivir. Res. 2023, 212, 105557. [Google Scholar] [CrossRef]
- Lösing, J.; Häge, S.; Schütz, M.; Wagner, S.; Wardin, J.; Sticht, H.; Marschall, M. ‘Shared-Hook’ and ‘Changed-Hook’ Binding Activities of Herpesviral Core Nuclear Egress Complexes Identified by Random Mutagenesis. Cells 2022, 11, 4030. [Google Scholar] [CrossRef] [PubMed]
- Alkhashrom, S.; Kicuntod, J.; Stillger, K.; Lützenburg, T.; Anzenhofer, C.; Neundorf, I.; Marschall, M.; Eichler, J. A Peptide Inhibitor of the Human Cytomegalovirus Core Nuclear Egress Complex. Pharmaceuticals 2022, 15, 1040. [Google Scholar] [CrossRef] [PubMed]
- Häge, S.; Marschall, M. ‘Come together’-The Regulatory Interaction of Herpesviral Nuclear Egress Proteins Comprises Both Essential and Accessory Functions. Cells 2022, 11, 1837. [Google Scholar] [CrossRef] [PubMed]
- Häge, S.; Büscher, N.; Pakulska, V.; Hahn, F.; Adrait, A.; Krauter, S.; Borst, E.M.; Schlötzer-Schrehardt, U.; Couté, Y.; Plachter, B.; et al. The Complex Regulatory Role of Cytomegalovirus Nuclear Egress Protein pUL50 in the Production of Infectious Virus. Cells 2021, 10, 3119. [Google Scholar] [CrossRef] [PubMed]
- Kicuntod, J.; Alkhashrom, S.; Häge, S.; Diewald, B.; Müller, R.; Hahn, F.; Lischka, P.; Sticht, H.; Eichler, J.; Marschall, M. Properties of Oligomeric Interaction of the Cytomegalovirus Core Nuclear Egress Complex (NEC) and Its Sensitivity to an NEC Inhibitory Small Molecule. Viruses 2021, 13, 462. [Google Scholar] [CrossRef] [PubMed]
- Häge, S.; Horsch, D.; Stilp, A.C.; Kicuntod, J.; Müller, R.; Hamilton, S.T.; Egilmezer, E.; Rawlinson, W.D.; Stamminger, T.; Sonntag, E.; et al. A quantitative nuclear egress assay to investigate the nucleocytoplasmic capsid release of human cytomegalovirus. J. Virol. Methods 2020, 283, 113909. [Google Scholar] [CrossRef] [PubMed]
- Häge, S.; Sonntag, E.; Borst, E.M.; Tannig, P.; Seyler, L.; Bäuerle, T.; Bailer, S.M.; Lee, C.P.; Müller, R.; Wangen, C.; et al. Patterns of Autologous and Nonautologous Interactions between Core Nuclear Egress Complex (NEC) Proteins of α-, β- and γ-Herpesviruses. Viruses 2020, 12, 303. [Google Scholar] [CrossRef]
- Muller, Y.A.; Häge, S.; Alkhashrom, S.; Höllriegl, T.; Weigert, S.; Dolles, S.; Hof, K.; Walzer, S.A.; Egerer-Sieber, C.; Conrad, M.; et al. High-resolution crystal structures of two prototypical β- and γ-herpesviral nuclear egress complexes unravel the determinants of subfamily specificity. J. Biol. Chem. 2020, 295, 3189–3201. [Google Scholar] [CrossRef]
- Schweininger, J.; Kriegel, M.; Häge, S.; Conrad, M.; Alkhashrom, S.; Lösing, J.; Weiler, S.; Tillmanns, J.; Egerer-Sieber, C.; Decker, A.; et al. The crystal structure of the varicella-zoster Orf24-Orf27 nuclear egress complex spotlights multiple determinants of herpesvirus subfamily specificity. J. Biol. Chem. 2022, 298, 101625. [Google Scholar] [CrossRef]
- Walzer, S.A.; Egerer-Sieber, C.; Sticht, H.; Sevvana, M.; Hohl, K.; Milbradt, J.; Muller, Y.A.; Marschall, M. Crystal Structure of the Human Cytomegalovirus pUL50-pUL53 Core Nuclear Egress Complex Provides Insight into a Unique Assembly Scaffold for Virus-Host Protein Interactions. J. Biol. Chem. 2015, 290, 27452–27458. [Google Scholar] [CrossRef]
- Sayana, S.; Khanlou, H. Maraviroc: A new CCR5 antagonist. Expert. Rev. Anti-Infect. Ther. 2009, 7, 9–19. [Google Scholar] [CrossRef] [PubMed]
- Tejada, S.; Martinez-Reviejo, R.; Karakoc, H.N.; Peña-López, Y.; Manuel, O.; Rello, J. Ribavirin for Treatment of Subjects with Respiratory Syncytial Virus-Related Infection: A Systematic Review and Meta-Analysis. Adv. Ther. 2022, 39, 4037–4051. [Google Scholar] [CrossRef] [PubMed]
- Kang, C.; Syed, Y.Y. Bulevirtide: First Approval. Drugs 2020, 80, 1601–1605. [Google Scholar] [CrossRef]
- Degasperi, E.; Anolli, M.P.; Lampertico, P. Bulevirtide-based treatment strategies for chronic hepatitis delta: A review. J. Viral. Hepat. 2023, 30 (Suppl. S1), 26–32. [Google Scholar] [CrossRef] [PubMed]
- Schang, L.M. Cyclin-dependent kinases as cellular targets for antiviral drugs. J. Antimicrob. Chemother. 2002, 50, 779–792. [Google Scholar] [CrossRef] [PubMed]
- Schang, L.M. Discovery of the antiviral activities of pharmacologic cyclin-dependent kinase inhibitors: From basic to applied science. Expert Rev. Anti-Infect. Ther. 2005, 3, 145–149. [Google Scholar] [CrossRef] [PubMed]
- Schang, L.M. First demonstration of the effectiveness of inhibitors of cellular protein kinases in antiviral therapy. Expert Rev. Anti-Infect. Ther. 2006, 4, 953–956. [Google Scholar] [CrossRef]
- Kapasi, A.J.; Spector, D.H. Inhibition of the cyclin-dependent kinases at the beginning of human cytomegalovirus infection specifically alters the levels and localization of the RNA polymerase II carboxyl-terminal domain kinases cdk9 and cdk7 at the viral transcriptosome. J. Virol. 2008, 82, 394–407. [Google Scholar] [CrossRef]
- Tamrakar, S.; Kapasi, A.J.; Spector, D.H. Human cytomegalovirus infection induces specific hyperphosphorylation of the carboxyl-terminal domain of the large subunit of RNA polymerase II that is associated with changes in the abundance, activity, and localization of cdk9 and cdk7. J. Virol. 2005, 79, 15477–15493. [Google Scholar] [CrossRef]
HCMV 1 | MCMV-UL97 2 | GPCMV 3 | RhCMV 4 | ||
---|---|---|---|---|---|
EC50 [µM] | MBV | 0.348 ± 0.420 | 1.797 ± 0.623 | 36.717 ± 27.270 | 7.532 ± 1.039 |
LDC | 0.009 ± 0.002 | 0.012 ± 0.008 | 0.044 ± 0.018 | 0.018 ± 0.017 | |
CIwt | 0.36 ± 0.22 | 0.32 ± 0.07 | 0.31 ± 0.01 | 0.75 ± 0.11 |
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Wild, M.; Karner, D.; Eickhoff, J.; Wagner, S.; Kicuntod, J.; Chang, W.; Barry, P.; Jonjić, S.; Lenac Roviš, T.; Marschall, M. Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers. Pharmaceutics 2023, 15, 2680. https://doi.org/10.3390/pharmaceutics15122680
Wild M, Karner D, Eickhoff J, Wagner S, Kicuntod J, Chang W, Barry P, Jonjić S, Lenac Roviš T, Marschall M. Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers. Pharmaceutics. 2023; 15(12):2680. https://doi.org/10.3390/pharmaceutics15122680
Chicago/Turabian StyleWild, Markus, Dubravka Karner, Jan Eickhoff, Sabrina Wagner, Jintawee Kicuntod, William Chang, Peter Barry, Stipan Jonjić, Tihana Lenac Roviš, and Manfred Marschall. 2023. "Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers" Pharmaceutics 15, no. 12: 2680. https://doi.org/10.3390/pharmaceutics15122680