Disrupting the OTUD4-USP7 deubiquitinase complex to suppress herpesvirus replication: a novel antiviral strategy

Abstract

The development of effective and broad-spectrum antiviral therapies remains an unmet need. Current virus-targeted antiviral strategies are often limited by narrow spectrum of activity and the rapid emergence of resistance. As a result, there is increasing interest in alternative approaches that target host cell factors critical for viral replication. One promising strategy is the targeting of deubiquitinases (DUBs), enzymes that regulate key host and viral proteins involved in viral reactivation and replication. In this study, we explore the potential of targeting a DUB complex for antiviral therapy based on our previous study. Our previous work revealed that the OTUD4-USP7 DUB complex plays a crucial role in KSHV lytic reactivation. Here, we developed a peptide, p8, which effectively disrupts the interaction between OTUD4 and USP7, leading to decreased abundance of the key viral transcription factor, RTA, and suppression of murine herpesviruses replication in vivo. These findings underscore the OTUD4-USP7 DUB complex as a promising host-targeting antiviral therapeutic target for the treatment of KSHV-associated malignancies. Moreover, our study highlights the potential of DUB-targeting therapies as a novel and effective strategy for the development of broad-spectrum antiviral agents.