Abstract
The development of broad-spectrum antivirals remains a major challenge in global health, as most existing antiviral drugs target virus-specific proteins and are therefore ineffective against unrelated viruses. As emerging and re-emerging viruses prioritized by the World Health Organization (WHO) continue to threaten global health security, there is an urgent need for alternative therapeutic strategies capable of targeting multiple viral pathogens. Host-directed antivirals offer one such approach by disrupting host factors required for viral replication, thereby enabling broader antiviral activity while reducing the likelihood of antiviral resistance. One promising target is heat shock protein 70 (HSP70), a molecular chaperone that plays a central role in protein folding, stabilization, and trafficking within the cellular proteostasis network. Many viruses exploit HSP70 to support essential stages of their replication cycles, including protein folding, assembly, and virion production. This widespread reliance on HSP70 suggests that perturbing the HSP70 proteostasis network may represent a promising strategy for broad-spectrum antiviral development. However, despite this potential, important knowledge gaps remain. It remains unclear to what extent HSP70 dependence is conserved across diverse WHO priority viruses and which stages of the viral lifecycle are most susceptible to disruption upon targeting HSP70. Furthermore, although several HSP70 inhibitors have been developed, it is not yet clear which compounds most effectively target this network while maintaining an acceptable therapeutic window. To address these gaps, this review synthesizes recent primary literature to evaluate the potential of the HSP70 proteostasis network as a host-directed antiviral target and to assess whether the small-molecule TH6744 is an effective inhibitor of this pathway and how its antiviral efficacy could be optimized. This analysis supports the role of HSP70 as a promising host-directed antiviral target and identifies TH6744 as a particularly promising inhibitor of this pathway. Collectively, these insights advance our understanding of how viruses exploit host proteostasis machinery and inform the development of host-directed antiviral strategies for emerging viral threats, thereby improving pandemic preparedness.