The VCP protein and Orthoflaviviruses: Impacts of VCP on viral replication and pathogenesis

Orthoflavivirus infections represent a major public health issue. While dengue virus (DENV) causes the most widespread-and potentially fatal-arthropod-borne viral disease, in utero Zika virus (ZIKV) infection can lead to severe neurological complications in newborns, including microcephaly. Given the lack of available treatments, identifying new therapeutic targets is essential. To create an intracellular environment conducive to viral replication, Orthoflaviviruses induce the formation of organelle-like replication factories (RFs) through mechanisms that remain poorly understood. We recently identified VCP (valosin-containing protein) as a binding partner for the non-structural protein 4B (NS4B) of both DENV and ZIKV, noting that VCP and NS4B colocalize within these replication factories. Importantly, inhibiting VCP ATPase activity impairs Orthoflavivirus replication by disrupting viral RF biogenesis, a process that correlates with enhanced virus-induced cell death. VCP inhibitors are currently undergoing clinical trials for cancer treatment; consequently, repurposing these drugs as antivirals for Orthoflavivirus infections is a promising avenue. We propose to investigate the molecular interaction between VCP and several clinically significant Orthoflaviviruses, such as DENV and ZIKV. We will also evaluate the therapeutic potential of VCP-targeting drugs against ZIKV pathogenesis in a murine infection model, thereby paving the way for the development of novel antiviral treatment strategies.