A replicative helicase as a putative new target for antiviral treatments

Fellow project opportunities:   What?

• The goal of the project is to identify novel inhibitory compounds for a viral helicase essential for replication and propagation of the widespread Herpes simplex viruses type 1 and type 2 (HSV-1/2). We will identify leads for such inhibitors and define their mode-of-action. Additionally, we will seek to improve their pharmacodynamic and pharmacokinetic properties in order to strengthen their potential for use in antiherpetic treatment in the future.

How?

• The target protein will be recombinantly purified from insect cells. In collaboration with the DTU Screening Core HTS platform, a functional assay will be established as a read out for subsequent high-throughput compound screening. The screen will aim to identify novel inhibitors of the viral helicase. The hit compounds will then be verified in functional biochemical assays and in a cellular model. Furthermore, we will assess how the compounds interact with the viral helicase to block function using single particle cryo-EM. Eventually, the compounds will be optimized in collaboration with the group of Mads H. Clausen to improve specificity, efficacy, and ADME properties.

Why?

• Human herpesviruses (HHVs) are one of the most widespread infections worldwide causing a range of diseases such as cold sores, mononucleosis, or even cancer. Lytic replication is a critical step in the viral life cycle and essential for viral survival in the human population. Antiherpetic medications such as the widely used nucleoside analogue acyclovir exclusively inhibit the viral DNA polymerase. However, resistance to current nucleoside analogues is emerging and alternative therapies remain scarce. In this project, we aim to identify alternative protein targets and new compounds for antiviral treatment.

  Interdisciplinary aspects of the project:

• This project will combine functional biochemistry and structural studies with high-throughput screening and medicinal chemistry to identify novel antiherpetic compounds and decipher their mode-of-action. The project will be carried out between the research group of Eva Kummer located in the Department of Health and Medical Sciences at the University of Copenhagen, and the group of Mads Hartvig Clausen from the Department of Chemistry at DTU. It will profit from state-of-the-art infrastructures at both sites including high-end microscopes for cryogenic electron microscopy and a fully automatic infrastructure for HTS.
• Based on preliminary data in the Kummer group, the candidate will establish functional assays in the Kummer group that can be used as a read-out for high-throughput screening (HTS) to identify inhibitory compounds against the viral helicase. Training of the candidate in HTS will take place in the Clausen lab. The analysis of the HTS results as well as the verification of putative hits in biochemical and cellular assays will combine the expertise of the Clausen group in medicinal chemistry and of the Kummer group in functional biochemistry and herpes virus research. Eventually, the binding site of the compound in the helicase will be identified by the candidate using single particle cryo-EM in the Kummer group. The structural insights will then be used to chemically optimize the compound for more efficient and specific binding to the viral helicase in collaboration with the Clausen group. Success of this project requires close collaboration between the interdisciplinary expertise present in the Kummer and Clausen labs. To be successful in this project, the candidate will therefore require a strong interdisciplinary mindset.