Project A1: Manfred Marschall

Virology

Head of Institute:
Prof. Dr. med. Klaus Überla

CDK7 kinase pathways as a drug targeting strategy for broad antiherpesviral intervention

Herpesviruses have evolved effective regulatory properties to modulate the host cell cycle. These include reprogramming activities towards the normal function of cyclin-dependent kinases (CDKs), which have pivotal importance for an efficient viral replication. Recent studies underlined the efficacy of CDK inhibitors as novel antiherpesviral drug candidates and the power of innovative methods and technologies in antiviral research. Importantly, herpes­viruses additionally express viral CDK orthologs, such as the cytomegalovirus-encoded kinase pUL97. The latter interacts with host cyclins, interferes with CDK-specific regulatory pathways and has been validated as a drug target in both experimental and clinical stages of drug development. In previous studies, we developed and characterized novel selective CDK7 as well as pUL97 inhibitors that exert a pronounced antiviral activities.

The project aims at gaining insight into CDK/cyclin-related complexes by the identification and subsequent functional characterization of associated viral and cellular proteins (Fig. 1). Specifically, small molecules targeting CDK7 or CDK7-induced pathways will be used as tools to identify the functional role of CDK7 during the replication of cytomegalovirus (CMV). Four work packages are planned to generate data on the mutual interregulation between CMV and CDK7, which will provide a basis for the evaluation of a CDK7-targeted intervention strategy. In the specific work packages, we will address the CDK7-mediated cell cycle modulation during CMV infection (WP I), the phosphorylation status of CDKs, cyclins and viral proteins possibly contained in CDK7-cyclin H complexes (WP II), the functional role of CDK7 in transcriptional regulation of CMV-infected cells (WP IIII), and the antiviral efficacy of kinase inhibitors applied in mouse/CMV in vivo experiments (WP IV). These experiments will help to define the importance of CDK7 and its drown-stream functions for CMV infection and for a putative exploitation as an antiviral targeting strategy.

Fig. 1. The postulated central role of CDK7 in controling three important points of virus-host interaction, i.e. the cell cycle, transcription and coregulation of viral proteins. CDK7 is both a CDK-activating kinase, which phosphorylates CDKs within their activation segment (T-loop), and a component of the cellular transcription machinery (TFIIH), which phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAP II). In addition, a role of CDK7 in the phospho-regulation of viral proteins and virus-induced cellular proteins is highly suggestive and will be addressed. WP I to WP IV, work packages.
 
Contact
Prof. Dr. rer. nat. Manfred Marschall
phone: +49 9131 85-26089
e-mail: manfred.marschall@fau.de
business card