SUMOylation of Viral Proteins: A Promising Host-Directed Antiviral Strategy

Infectious viruses pose significant health concerns globally. In the recent decade, numerous pandemics and outbreaks have emerged, costing millions of lives and immense financial burdens. The World Health Organization (WHO) has highlighted the need for pandemic preparedness, with a list of WHO priority pathogens including high-priority viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ZIKA virus (ZIKV). Antiviral drug resistance remains a major challenge due to the evolving nature of viruses, diminishing direct-acting antivirals over time. To overcome drug resistance, host- directed antivirals (HDAs) are key in preparing for the next pandemic. As viruses rely on the host's protein synthesis machinery, many viral proteins undergo post-translational modifications (PTMs) to facilitate infection. PTMs are covalent alterations to proteins after biosynthesis and are essential for cellular functions such as growth, metabolism, and cell signaling. SUMOylation is a ubiquitination-like PTM that regulates various host processes, including cellular localization, transcription regulation, and protein-protein interactions. This pathway involves the covalent attachment of a small ubiquitin-like modifier (SUMO) polypeptide to a lysine residue on the target protein. Recent studies have highlighted that numerous viruses, including ZIKV and SARS-CoV-2, exploit the SUMOylation pathway to suppress host immune responses and facilitate infection. ZIKV manipulates SUMOylation to stabilize viral proteins, thereby enhancing replication, while SARS-CoV-2 modifies its nucleocapsid protein (SARS2-NP) to disrupt innate immunity. Both viruses alter interferon-beta (IFN-β) production, a critical component of antiviral defense, allowing for viral immune evasion. Beyond ZIKV and SARS-CoV-2, other WHO-priority viruses have shown to interact with SUMOylation to inhibit antiviral responses and support viral replication. The growing evidence of SUMOylation's role in viral pathogenesis highlights its potential as a novel therapeutic target. SUMOylation inhibitors, which were initially developed for cancer treatment, have demonstrated potential in disrupting SUMOylation and exhibiting antiviral capacities. TAK-981, a SUMO E1 inhibitor currently in Phase I/II clinical trials, has shown safety and tolerability in patients. SUMOylation inhibitors could be repurposed against emerging viral threats. Understanding how these viruses manipulate the SUMOylation pathway can allow for the development of HDA strategies, which can ultimately streamline processes for the next pandemic.