Abstract
Viral infections remain a major global health threat, with many emerging pathogens posing ongoing risks to public health. While direct-acting antivirals (DAAs) have demonstrated efficacy against specific viruses, their pathogen-specific nature limits rapid responses to new threats. In contrast, host-directed antivirals (HDAs) target conserved host cellular pathways exploited by viruses, offering potential for broad-spectrum antiviral activity. The World Health Organization (WHO) priority pathogen framework highlights the continued emergence of high-risk RNA viruses, underscoring the need for innovative therapeutic strategies.
One conserved pathway is intracellular trafficking, particularly coat protein complex I (COPI)-mediated retrograde transport between the Golgi apparatus and endoplasmic reticulum (ER). This pathway is essential for maintaining cellular homeostasis and is conserved across eukaryotic systems. Many viruses exploit host trafficking machinery to support protein maturation, intracellular transport, and virion assembly, suggesting that these pathways represent shared vulnerabilities across viral families.
The COPI complex, a heptameric coatomer regulated by the small guanosine triphosphatase (GTPase) ADP-ribosylation factor 1 (Arf1), mediates vesicle formation and cargo selection within the early secretory pathway. Its central role in intracellular transport makes it an attractive host-directed antiviral target. However, current pharmacological inhibitors, such as Brefeldin A and Golgicide A, broadly inhibit Arf1 activation upstream of COPI coat assembly and are associated with significant cytotoxicity, highlighting the need for more selective strategies.
We hypothesize that COPI-mediated trafficking represents a critical host dependency for viral replication, and that selective disruption of COPI-specific interactions can inhibit viral processes while minimizing host toxicity. To address this, this study aims to (1) evaluate the antiviral potential of targeting COPI-mediated retrograde transport across viral systems, and (2) identify strategies to screen for reversible small-molecule inhibitors that selectively target COPI machinery, particularly the β-COP–Arf1 interface. Advances in artificial intelligence and machine learning (AI/ML), combined with high-resolution structural characterization and virtual screening, will enable identification of candidate compounds that bind key interaction sites within the COPI pathway. Promising inhibitors will be assessed using cytotoxicity assays, antiviral efficacy testing, and validation of target engagement.
Overall, targeting COPI-mediated transport represents a promising host-directed antiviral strategy with broad-spectrum potential, addressing key limitations of current antiviral approaches.