Restoring DNASEs antiviral potential

Every individual carries at least a herpesvirus causing mild to serious diseases without definitive cure.

Although in theory, herpesvirus genomes can be degraded by host DNA nucleases (DNASEs), the ER preliminary data has evidenced DNASE2B protein levels to decrease upon herpes simplex virus-1 (HSV-1) infection.

In order to restore DNASEs anti-viral potential, REDAVIP aims to 1) uncover the susceptibility of DNASEs to HSV-1, 2) gain mechanistic insights of HSV-1 proteins and DNASEs interaction, and 3) screen drugs restoring host DNASEs so the vDNA can be cleared from the organism.

To do so, REDAVIP will assess DNASEs’ endogenous levels upon infection by immunoblot and enrich them with immunoprecipitation to identify interacting viral protein(s) by mass spectrometry collaborating internationally.

Afterwards, their minimal interacting surfaces will be determined and disrupted with in silico drug library screens collaborating internationally.

Then, a tripartite fluorescence complementation assay will confirm the disruption of this pathogenic interaction in cellula.

Candidate compounds restoring the DNASEs ability of degrading vDNA will be validated by plaque assays for IP protection, since they may represent a first step towards an overdue cure against herpesviral infections and life quality improvement, especially for an ageing population.

Given the ambitious and novel objectives, the ER applies her multidisciplinary expertise to propose mitigation strategies that will ensure experimental feasibility and multiple outputs.

This work will allow the ER to transfer her knowledge acquired through European laboratories to the acceptor institution, and progress from basic to translational research to learn and ensure a revenue of invested funds. The findings will be broadly disseminated to improve the ER soft skills.

Uncovering how host DNASEs are impaired during herpesvirus infection using HSV-1 as a model is an asset to find novel antivirals against further viruses.