Which substances can inhibit the multiplication and survival of herpes viruses in the body?

What is this research project about?

Herpes viruses can cause zoster.

What is this research project about?

Herpes viruses can cause a number of diseases such as chickenpox, shingles, herpes encephalitis, neonatal infections and Pfeiffer’s glandular fever. They pose a serious threat to susceptible and immunocompromised individuals such as newborns, the elderly, transplant recipients and people with other immunodeficiencies or concurrent infections. For example, cytomegalovirus (HCMV) can cause severe disease in transplant recipients, and Kaposi’s Sarcoma Herpesvirus (KSHV) and Epstein-Barr virus (EBV) can cause cancer.

We aim to expand the portfolio of currently available antiviral agents. Additional inhibitors could enable new therapeutic options, thereby suppressing viral replication in persistent infections or even eliminating the infection.

What’s the current status?

There are many antiviral drugs against herpes viruses. They inhibit the replication of the viral genome and in this way stop the virus replicating – but unfortunately not completely or permanently, so that the infection cannot be eliminated. With one exception, all currently available antiviral drugs block viral DNA polymerase, the viral DNA synthesis machinery needed during viral replication.

However, these drugs are not efficient enough to permanently suppress viral replication or eliminate the infection. Very often, this results in persistent expression of the viral genome, which can contribute to disease development.

Kaposi’s Sarkoma Herpes Virus capsid structure, which serves to package the viral genome.

What are the project goals?

If we could specifically interrupt the viral life cycle at other points, it would be possible to develop more effective therapies for the affected individuals. In particular, it would be desirable to stop the viral life cycle at a very early stage. This is because viral genes and proteins that arise in early stages of the viral life cycle can contribute to disease initiation and are responsible for the ability of these viruses to persist long-term in the infected person.

For example, we want to investigate the following points in the viral life cycle as potential drug targets: The KSHV latency protein LANA, the CATC protein complex on herpesviral capsids and the auxiliary proteins of viral DNA polymerase.

The ability to target these and inhibit their function with small synthetic molecules would greatly improve our ability to develop new and more effective combination therapies.

How do we get there?

From our more than 25 years of experience with various herpes viruses, we have learned a lot about how the virus manages to establish a long-lasting infection, escape recognition by the host’s immune system and be transmitted from mother to daughter cell during cell division. For example, the viral protein LANA of KSHV mediates many of these functions and it can reprogramme the infected cell in favour of the virus. Therefore, we are exploring the structure of LANA in more detail and also the nature of tiny “territories” in the nucleus of the infected cell where the virus resides in latent form. We have also characterised the function of the viral membrane protein pK15, which is necessary in early phases of replication. We have developed first-generation inhibitors for both LANA and pK15. Now we want to transfer these findings and experiences to other herpesviruses such as the β-herpesvirus HCMV.

Another attractive drug target is the CATC protein complex of the virus assembly. This structure is potentially applicable for a broad-spectrum approach. It has already been solved for herpes simplex virus (HSV-1) by cryo-electron microscopy.

An equally interesting antiviral target, which could also allow a broad-spectrum approach, are the auxiliary proteins of viral DNA polymerase. They act as processivity factors in viral replication. We are exploring whether these factors and its homologues from other herpesviruses are suitable as potential antiviral target proteins.

Structure of the complex that the Kaposi’s Sarcoma Herpes Virus protein LANA forms with DNA.

Projectleaders

Project title: Innovative target molecules for inhibiting herpesviral infections

Prof. Dr. Thomas F. Schulz

Prof. Dr. Thomas Krey

Projekte: B10, D1

Prof. Dr. Martin Messerle

Projekte: D1, D2

Prof. Dr. Kay Grünewald

Projekte: D1, D2

Dr. Martin Empting

Projects: C3, D1

Prof. Dr. Beate Sodeik

Projekte: A4, D1, D2

Prof. Dr. Anna K. H. Hirsch

Project: D1

Publications of the Project D1

Publications 2023

Disrupting Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) Latent Replication with a Small Molecule Inhibitor. Berwanger A, Stein SC, Kany AM, Gartner M, Loretz B, Lehr CM, Hirsch AKH, Schulz TF, Empting M. J Med Chem. 2023 Aug 10;66(15):10782-10790.

Kaposi sarcoma-associated herpesvirus latency-associated nuclear antigen: more than a key mediator of viral persistence. Schulz TF, Freise A, Stein SC.  Curr Opin Virol. 2023 Aug;61:101336. doi: 10.1016/j.coviro.2023.101336. Epub 2023 Jun 16. PMID: 37331160.

The role of nuclear pores and importins for herpes simplex virus infection. Döhner K, Serrero MC, Sodeik B.  Curr Opin Virol. 2023 Oct;62:101361. doi: 10.1016/j.coviro.2023.101361. Epub 2023 Sep 4. PMID: 37672874.

Publications 2022

pUL36 Deubiquitinase Activity Augments Both the Initiation and the Progression of Lytic Herpes Simplex Virus Infection in IFN-Primed Cells. Mohnke J, Stark I, Fischer M, Fischer PM, Schlosser A, Grothey A, O’Hare P, Sodeik B, Erhard F, Dölken L, Hennig T.  J Virol. 2022 Nov 23;96(22):e0096322. doi: 10.1128/jvi.00963-22. Epub 2022 Oct 31. PMID: 36314822; PMCID: PMC9683058.

Publications 2021

The journey of herpesvirus capsids and genomes to the host cell nucleus. Döhner K, Cornelius A, Serrero MC, Sodeik B. Curr Opin Virol. 2021 Oct;50:147-158. doi: 10.1016/j.coviro.2021.08.005. Epub 2021 Aug 28. PMID: 34464845.

Recent Advances in Developing Treatments of Kaposi’s Sarcoma Herpesvirus-Related Diseases. Naimo E, Zischke J, Schulz TF.  Viruses. 2021 Sep 9;13(9):1797. doi: 10.3390/v13091797. PMID: 34578378; PMCID: PMC8473310.

Recruitment of phospholipase Cγ1 to the non-structural membrane protein pK15 of Kaposi Sarcoma-associated herpesvirus promotes its Src-dependent phosphorylation. Samarina N, Ssebyatika G, Tikla T, Waldmann JY, Abere B, Nanna V, Marasco M, Carlomagno T, Krey T, Schulz TF. PLoS Pathog. 2021 Jun 18;17(6):e1009635. doi: 10.1371/journal.ppat.1009635. eCollection 2021 Jun. PMID: 34143834 Free PMC article.

Assembly of infectious Kaposi’s sarcoma-associated herpesvirus progeny requires formation of a pORF19 pentamer. Naniima P, Naimo E, Koch S, Curth U, Alkharsah KR, Ströh LJ, Binz A, Beneke JM, Vollmer B, Böning H, Borst EM, Desai P, Bohne J, Messerle M, Bauerfeind R, Legrand P, Sodeik B, Schulz TF, Krey T. PLoS Biol. 2021 Nov 4;19(11):e3001423.

Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity. Zapatero-Belinchón, F.J.; Ötjengerdes, R.; Sheldon, J.; Schulte, B.; Carriquí-Madroñal, B.; Brogden, G.; Arroyo-Fernández, L.M.; Vondran, F.W.R.; Maasoumy, B.; von Hahn, T.; Gerold, G. Cells 2021, 10, 1626.

3D culture conditions support Kaposi’s sarcoma herpesvirus (KSHV) maintenance and viral spread in endothelial cells. Dubich T, Dittrich A, Bousset K, Geffers R, Büsche G, Köster M, Hauser H, Schulz TF, Wirth D. J Mol Med (Berl). 2021 Mar;99(3):425-438. doi: 10.1007/s00109-020-02020-8. Epub 2021 Jan 23. PMID: 33484281 Free PMC article.

DNA origami signposts for identifying proteins on cell membranes by electron cryotomography. Silvester E, Vollmer B, Pražák V, Vasishtan D, Machala EA, Whittle C, Black S, Bath J, Turberfield AJ, Grünewald K, Baker LA. Cell. 2021 Feb 18;184(4):1110-1121.e16. doi: 10.1016/j.cell.2021.01.033. PMID: 33606980; PMCID: PMC7895908.

Phenotypical Characterization of the Nuclear Egress of Recombinant Cytomegaloviruses Reveals Defective Replication upon ORF-UL50 Deletion but Not pUL50 Phosphosite Mutation. Häge S, Sonntag E, Svrlanska A, Borst EM, Stilp AC, Horsch D, Müller R, Kropff B, Milbradt J, Stamminger T, Schlötzer-Schrehardt U, Marschall M. Viruses. 2021 Jan 22;13(2):165. doi: 10.3390/v13020165. PMID: 33499341; PMCID: PMC7911381.

The Complex Regulatory Role of Cytomegalovirus Nuclear Egress Protein pUL50 in the Production of Infectious Virus. Häge S, Büscher N, Pakulska V, Hahn F, Adrait A, Krauter S, Borst EM, Schlötzer-Schrehardt U, Couté Y, Plachter B, Marschall M.  Cells. 2021 Nov 11;10(11):3119. doi: 10.3390/cells10113119. PMID: 34831342; PMCID: PMC8625744.

Freiburg index of post-TIPS survival (FIPS) a valid prognostic score in patients with cirrhosis but also an advisor against TIPS? Stockhoff L, Schneider H, Tergast TL, Cornberg M, Maasoumy B. J Hepatol. 2021 Aug;75(2):487-489. doi: 10.1016/j.jhep.2021.02.031. Epub 2021 Mar 12. PMID: 33716088.

IgG, a novel predictor for acute-on-chronic liver failure and survival in patients with decompensated cirrhosis? Tergast TL, Schultalbers M, Wedemeyer H, Cornberg M, Maasoumy B. J Hepatol. 2021 Jul;75(1):229-231. doi: 10.1016/j.jhep.2021.01.040. Epub 2021 Feb 4. PMID: 33548386.

Publications 2020

Targeting Kaposi’s Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use. J Virol. Beauclair G, Naimo E, Dubich T, Rückert J, Koch S, Dhingra A, Wirth D, Schulz TF. 2020 Feb 14;94(5):e01791-19. doi: 10.1128/JVI.01791-19. PMID: 31826996; PMCID: PMC7022342.

Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease. Lang J, Bohn P, Bhat H, Jastrow H, Walkenfort B, Cansiz F, Fink J, Bauer M, Olszewski D, Ramos-Nascimento A, Duhan V, Friedrich SK, Becker KA, Krawczyk A, Edwards MJ, Burchert A, Huber M, Friebus-Kardash J, Göthert JR, Hardt C, Probst HC, Schumacher F, Köhrer K, Kleuser B, Babiychuk EB, Sodeik B, Seibel J, Greber UF, Lang PA, Gulbins E, Lang KS. Nat Commun. 2020 Mar 12;11(1):1338. doi: 10.1038/s41467-020-15072-8. PMID: 32165633; PMCID: PMC7067866.

Quantitative Proteomics Analysis of Lytic KSHV Infection in Human Endothelial Cells Reveals Targets of Viral Immune Modulation Gabaev I, Williamson JC, Crozier TWM, Schulz TF, Lehner PJ.  Cell Rep 2020;33(2):108249

Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi’s Sarcoma-Associated Herpesvirus ACS Kirsch P, Jakob V, Elgaher WAM, Walt C, Oberhausen K, Schulz TF, Empting M.  Chem Biol 2020;15(2):388-395

Hit-to-lead optimization of a latency-associated nuclear antigen inhibitor against Kaposi’s sarcoma-associated herpesvirus infections Kirsch P, Stein SC, Berwanger A, Rinkes J, Jakob V, Schulz TF, Empting M.  Eur J Med Chem 2020;202:112525 

Brd/BET Proteins Influence the Genome-Wide Localization of the Kaposi’s Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus Major Latency Proteins Lotke R, Schneeweiss U, Pietrek M, Günther T, Grundhoff A, Weidner-Glunde M, Schulz TF.  Front Microbiol 2020;11:591778

Whole-Genome Approach to Assessing Human Cytomegalovirus Dynamics in Transplant Patients Undergoing Antiviral Therapy Suarez NM, Blyth E, Li K, Ganzenmueller T, Camiolo S, Avdic S, Withers B, Linnenweber-Held S, Gwinner W, Dhingra A, Heim A, Schulz TF, Gunson R, Gottlieb D, Slobedman B, Davison AJ.  Front Cell Infect Microbiol 2020;10:267

Cellular Electron Cryo-Tomography to Study Virus-Host Interactions. Quemin ERJ, Machala EA, Vollmer B, Pražák V, Vasishtan D, Rosch R, Grange M, Franken LE, Baker LA, Grünewald K. Annu Rev Virol. 2020 Sep 29;7(1):239-262. doi: 10.1146/annurev-virology-021920-115935. Epub 2020 Jul 6. PMID: 32631159.

The Proteome and Secretome of Cortical Brain Cells Infected With Herpes Simplex Virus Front. Niko Hensel, Verena Raker, Benjamin Förthmann, Anna Buch, Beate Sodeik, Andreas Pich, Peter Claus, Neurol., 27 August 2020, Sec. Neuroinfectious Diseases, Volume 11 – 2020, https://doi.org/10.3389/fneur.2020.00844

Publications 2019

Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi’s Sarcoma-Associated Herpesvirus/Human Herpesvirus 8. Kirsch P, Jakob V, Oberhausen K, Stein SC, Cucarro I, Schulz TF, Empting M. J Med Chem. 2019 Apr 25;62(8):3924-3939. doi: 10.1021/acs.jmedchem.8b01827. Epub 2019 Apr 12. PMID: 30888817.

Kaposi’s sarcoma-associated herpesvirus vIRF2 protein utilizes an IFN-dependent pathway to regulate viral early gene expression Koch S, Damas M, Freise A, Hage E, Dhingra A, Rückert J, Gallo A, Kremmer E, Tegge W, Brönstrup M, Brune W, Schulz TF. PLoS Pathog 2019;15(5):e1007743 D1

Autophagic degradation of lamins facilitates the nuclear egress of herpes simplex virus type 1. Turan A, Grosche L, Krawczyk A, Mühl-Zürbes P, Drassner C, Düthorn A, Kummer M, Hasenberg M, Voortmann S, Jastrow H, Dörrie J, Schaft N, Kraner M, Döhner K, Sodeik B, Steinkasserer A, Heilingloh CS. J Cell Biol. 2019 Feb 4;218(2):508-523. doi: 10.1083/jcb.201801151. Epub 2018 Dec 26. PMID: 30587512; PMCID: PMC6363456.

Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi’s Sarcoma-Associated Herpesvirus/Human Herpesvirus 8 Philine Kirsch, Valentin Jakob, +4 authors M. Empting. Journal of Medicinal Chemistry. 19 March 2019 DOI:10.1021/acs.jmedchem.8b01827Corpus ID: 84183173

Publications of the Project D1