How can novel drug targets be identified?

What is this research project about?

What is this research project about?

Human herpes viruses are the causative agents of an array of diseases like chickenpox, Zoster, Herpes encephalitis, infections of the newborn, a range of diseases in immunocompromised patients, infectious mononucleosis. Two of the human herpesviruses, Epstein-Barr virus (EBV) and Kaposi Sarcoma Herpesvirus (KSHV), are recognized by WHO as class 1 carcinogens and cause a variety of human cancers, such as nasopharyngeal carcinoma, lymphoma and Kaposi’s sarcoma.

We want to improve the portfolio of currently available antiviral drugs. The availability of additional inhibitors targeting either persistence-related processes or the viral assembly stage within the viral life cycle might open up new therapeutic options to suppress viral replication during persistent infections or even eliminate a persisting infection.

What’s the current status?

Currently available drugs target the viral DNA polymerase and thereby inhibit the replication of the viral genome, but are often not effective enough to suppress viral replication permanently or eliminate the infection. In many cases, the available inhibitors still allow expression of viral genes that may contribute to pathogenesis. For example, KSHV replication can be curtailed by cidofovir, ganciclovir and foscarnet. However, these drugs are not effective against most KSHV-associated diseases, as they still allow the expression of viral proteins known to contribute to tumor formation.

What are the project goals?

In the frame of this project, we want to explore three novel steps as point-of-intervention in the viral life cycle:

  • A) capsid-associated tegument complex (CATC; virus assembly).

  • B) DNA polymerase accessory proteins (virus replication, but expected to be devoid of cross reactivity to established targets).

  • C) N-terminal domain of KSHV LANA (interaction partner of SMARCAL1 host protein; virus replication & persistence).

Being able to target these steps with small molecular entities would improve our ability to devise more efficacious forms of antiviral combination therapy for the affected patients.

How do we get there?

A) The CATC structure has been recently resolved for HSV-1 by Cryo-EM and comprises, among other features, an essential five-helix bundle motif involving three protein chains – pUL17, pUL25, and pUL36 (Dai et al. Science 2018). This protein-protein-interaction is described to be of pivotal importance for virus assembly and tegumentation, which renders it an attractive target that might be exploitable for a broad-spectrum antiherpesviral approach.

B) A similarly interesting and innovative antiherpesviral target may be summarized under the term DNA polymerase accessory proteins, which act as processivity factors in the viral DNA replication process (Weller et al. Expert Opin. Ther. Targets 2013). These proteins, which in case of HSV-1 are referred to as UL42, are reminiscent of the human PCNA sliding clamps. Notably, scientists at HIPS have recently validated the functional bacterial homolog DnaN as an antimycobacterial drug target (Kling et al. Science 2015). Hence, we want to exploit UL42 and its homologs in other herpesviruses as a potential target for novel, potentially broad-spectrum antiherpesviral drugs.

C) In the case of KSHV LANA, which is essential for viral latent replication and persistence, the Schulz and Empting groups have already successfully probed the C-terminal DNA-binding domain for druggability via a fragment-based approach. We were able to identify fragment-sized hits by means of biophysical screening and to optimize them into lead-like compounds, which inhibit the DNA-protein interaction in the low micromolar range (Kirsch et al. 2019). Now, we want to explore a different region of LANA located near the N-terminus for the possibility to interfere with viral replication and persistence. Preliminary data from the Schulz group show that this globular domain provides the platform for the interaction with a cellular annealing helicase.

Projectleaders

Project title: Tackling Innovative Drug Targets Against Herpesviral Infections

Dr. Martin Empting

Projekte: C3, D3

 
  Wirkstoffdesign und Optimierung, Helmholtz-Zentrum für Infektionsforschung (HZI)
 
  +49 681 98806-2031
 
 
  Martin.Empting
@helmholtz-hzi.de
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Prof. Dr. Thomas F. Schulz

Projekte: D1, D3

  Leiter
  Institut für Virologie, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-4107
  +49 511 532-8736
 
  Schulz.Thomas
@mh-hannover.de
  DOWNLOAD CV

Prof. Dr. Thomas Krey

Projekte: B10, D1, D3

 
  Institut für Biochemie, Universität Lübeck
  Ratzeburger Allee 160
23562 Lübeck
  +49-451-3101-3102
  +49-451-3101-3104
 
  krey@biochem.uni-luebeck.de
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Prof. Dr. Beate Sodeik

Projekte: A4, D2, D3

 
  Institut für Virologie, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-2846
 
 
  Sodeik.Beate
@mh-hannover.de
  DOWNLOAD CV

Project D3 Publications

Targeting the Kaposi Sarcoma Herpesvirus ORF 21 tyrosine kinase and viral lytic reactivation by tyrosine kinase inhibitors approved for clinical use. Beauclair G, Naimo E, Dubich T, Rückert J, Koch S, Dhingra A, Wirth D, Schulz TF. J Virol. 2019 Dec 11. pii: JVI.01791-19. doi: 10.1128/JVI.01791-19. [Epub ahead of print]

Publications published before the launch of RESIST:

Hellert J, Weidner-Glunde M, Krausze J, Lünsdorf H, Ritter C, Schulz TF*, Lührs T* (2015) The 3D-structure of Kaposi’s sarcoma herpesvirus LANA c-terminal domain bound to DNA. Proc Natl Acad Sci USA. 112: 6694-9.

Kirsch P, Jakob V,. Oberhausen K, Stein SC Cucarro I, Schulz TF, Empting M*, Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi’s Sarcoma-Associated Herpesvirus/Human Herpesvirus 8, Journal of Medicinal Chemistry (2019), 62, 3924-3939.

A Buch, O Müller, L Ivanova, K Döhner, D Bialy, JB Bosse, A Pohlmann, A Binz, M Hegemann, CH Nagel, M Koltzenburg, A Vieho-Borbolla, B Rosenhahn, R Bauerfeind & B Sodeik* (2017), Inner tegument proteins of Herpes Simplex Virus are sufficient for intracellular capsid motility but not for axonal targeting, PLoS Pathogens 13(12):e1006813.

Zhang G, Chan B, Samarina N, Abere B, Weidner-Glunde M, Buch A, Pich A, Brinkmann MB, Schulz TF (2016) Cytoplasmic isoforms of Kaposi Sarcoma Herpesvirus LANA recruit and antagonize the innate immune sensor cGAS. Proc Natl Acad Sci U S A. 113: E1034-43. doi: 10.1073/pnas.1516812113.

Abere B, Mamo TM, Hartmann S, Samarina N, Hage E, Rückert J, Hotop SK, Büsche G, Schulz TF (2017) The Kaposi Sarcoma-associated herpesvirus (KSHV) non-structural membrane protein K15 is required for viral lytic replication and may represent a therapeutic target. PLoS Pathogens. 13(9):e1006639. doi: 10.1371/journal.ppat.1006639.

Project D3
Publications