Institute of Virology

Duxdrugs – Development of DUX4-inhibitors for therapy of herpesviral infections

Herpesviridae are DNA viruses that can cause a variety of diseases in humans and animals. The family comprises nine human members, which are further classified into the three subfamilies of alpha-, beta- and gamma-herpes viruses. One hallmark of herpesviruses is the lifetime persistence in the infected host. The persistent viruses are normally controlled by the immune system to remain silent. Upon weakening of the immune system herpesviruses can reactivate and cause symptoms, which is associated with significant morbidity and mortality. As the variety of antiviral drugs is quite limited and resistance mutations arise frequently, there is an urgent need for broad-acting antivirals that can be used to treat herpesviral infection and reactivation.

We previously found that the germline transcription factor DUX4 is induced upon herpesviral infection. DUX4 is critical for a process during the early embryonic development, called zygotic genome activation. After the expression in the early development, DUX4 is normally silenced. The ectopic expression of DUX4 by herpesviruses induces a transcriptional program that is essential for herpesviral replication.

Our current research is focused on the rational design of novel anti-herpesviral drugs targeting DUX4. We attempt to identify an inhibitor of DUX4 that can prevent herpesviral zygotic genome activation and therefore can act against herpesviruses of all subfamilies. Simultaneously, we investigate the detailed mechanisms of DUX4 induction upon herpesviral infection.

Host- and restriction-factors of poxvirus infections

The family of Poxviruses comprises several members that cause disease in humans. Our group investigates host- and restriction-factors that are important for replication of various poxviruses (Vaccinia, Cowpox, Camelpox and Mpox) in human tissue. Mpox was previously thought to be a zoonotic disease endemic in parts of central, west, and east Africa, however the virus adapted to humans, resulting in an ongoing Mpox outbreak with human to human transmission and cases in more than 100 countries. Our research focuses on pathways that either promote or inhibit viral replication in order to develop antiviral therapeutics.

Collaboration Partners:

• Dr. Emanuel Wyler and Dr. Vedran Franke (Berlin Institute of Medical Systems Biology, Berlin, Germany)
• Prof. Dr. Georges Verjans, Dr. Michiel van Gent (Rotterdam, Netherlands)
• Dr. Alexander Hahn (DPZ, Göttingen, Germany)
• Prof. Dr. Thomas Stamminger (Ulm, Germany)
• Prof. Dr. Armin Ensser (Erlangen, Germany)
• Prof. Dr. Thomas Gramberg (Erlangen, Germany)
• Prof. Dr. Frank Stubenrauch (Tübingen, Germany)

Team Leader

Dr. rer. nat. Florian Full

Phone: +49 (0)761 270 83344

Current lab members (Phone: +49 (0)761 270 83346)

Pia Veratti, B. Sc. (Technician)

Jiang Tan, Ph.D (Postdoc)

Sandra Pennisi, Ph.D (Postdoc)

Eva Neugebauer, M. Sc. (Ph.D Student)

Melanie Schächtle, M. Sc. (Ph.D Student)

Aura María Bastidas Quintero, M. Sc.

Paula Faller, B. Sc.

Isabelle Welker (cand. med.)

Karla Stein

Benedikt Sachs

Selected Publications:

Tan J, Franke V, Neugebauer E, Lagisquet J, Kuderna AK, Walter S, Ensser A, Landthaler M, Stamminger T, Gramberg T, Akalin A, Wyler E and Full F. DNA virus infections shape transposable elements activity in vitro and in vivo. (2024) Preprint bioRxiv 2024.04.18.589901; doi: doi.org/10.1101/2024.04.18.589901
 

Neugebauer E, Bastidas-Quintero AM, Weidl D and Full F. Pioneer factors in viral infection. (2023) Front Immunol. 2023 Oct 9;14:1286617. doi: 10.3389/fimmu.2023.1286617. eCollection 2023.

Full F, Ensser A. (2019) Early Nuclear Events after Herpesviral Infection. J Clin Med. 2019 Sep 7;8(9). pii: E1408. doi: 10.3390/jcm8091408. Review

Full F, van Gent M, Sparrer KMJ, Chiang C, Zurenski MA, Scherer M, Brockmeyer NH, Heinzerling L, Stürzl M, Korn K, Stamminger T, Ensser A and Gack MU. (2019) Centrosomal protein TRIM43 restricts herpesvirus infection by regulating nuclear lamina integrity. Nature Microbiology, 2019 Jan;4(1):164-176.

Full F, Jungnickl D, Reuter N, Bogner E, Brulois K, Scholz B, Stürzl M, Myoung J, Jung JU, Stamminger T and Ensser A. (2014) Kaposi's sarcoma associated herpesvirus tegument protein ORF75 is essential for viral lytic replication and plays a critical role in the antagonization of ND10-instituted intrinsic immunity. PLoS Pathog. 10(1):e1003863.