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Project A1: Debora Obergfäll, associated doctoral researcher (PhD)

Investigation of specific targeting strategies to generate a mechanistically new type of antiviral drugs

The current repertoire of antiviral drugs is based on the classical type of direct-acting antivirals. Their limitations, in terms of viral drug resistance and pharmacological constraints have been clearly recognized so that alternatives are urgently needed. An innovative concept aims at the targeting of cellular proteins through host-directed antivirals, which has only rarely been realized so far. This situation prompted us to look out for specified strategies of drug targeting to improve antiviral drug mechanisms and efficacies, particularly against clinically highly relevant human viruses. In this context, we recently documented initial progress with new ways of chemical drug functionalization specified by 'Proteolysis Targeting Chimeras' (PROTACs). The chemical linkage of PROTAC moieties to bioactive small molecules has been used as a means to induce the proteasomal target protein degradation. This strategy is expected to improve the potency of antiviral drugs in a number of ways, i.e. by an increase of antiviral efficacies, the suppression of viral drug resistance and opening new options of broad-spectrum activities. Thus, the project is focused on the implementation of PROTAC-based targeting to generate a mechanistically new type of antiviral drugs. This PROTAC strategy might possess game-changing qualities in antiviral research within the near future. Our working hypothesis postulates that the efficacy of anti-herpesviral drugs may be improved by the chemical addition of PROTAC moieties, in order to achieve a mechanistically new way of target degradation.

This PhD project will be focused on three aims:

  1. Characterization of novel host-directed and direct-acting antivirals, in particular PROTAC-based small molecules, to present their mechanistic uniqueness
  2. Demonstration of an enhanced in vitro efficacy of the PROTAC-based antivirals directed against specifically interesting human pathogenic herpesviruses (HCMV, EBV, HHV-6)
  3. Assessment of the strong PROTAC-mediated potential to suppress the development of viral drug resistance and to provide a proof-of-concept.

To achieve these aims, several host-directed and direct-acting small molecules will be analyzed for their anti-HCMV efficacy. Concerning host factors different cyclin-dependent kinases, (CDK) and bromodomain-containing protein (BDR) will be targeted. This includes PROTACs based on CDK8, CDK7, CDK4/6, and BRD4 inhibitors. In the current HCMV therapy, maribavir (MBV), letermovir (LMV) and cidofovir (CDV) are important small molecules to treat HCMV infection by targeting viral replication. Based on this, direct-acting PROTACs based on MBV, LMV and CDV will be analyzed. In the case of a successful implementation of this PROTAC strategy, these experimental compounds may comprise enhanced antiviral activity, reduced resistance barrier, and a potential of broad-spectrum application.