Metal-binding proteins and proteases in RNA viruses: unravelling functional diversity and expanding therapeutic horizons
Authors: Dixit Himisha , Kulharia Mahesh , Verma Shailender Kumar 
Published: November 2023

ABSTRACT
Metal-binding proteins, including proteases, play critical roles in the replication and pathogenesis of RNA viruses. This study conducted a comprehensive analysis to elucidate the landscape of metalloproteins and identify metal-binding proteases within RNA viruses. The analysis revealed the presence of predicted metal-binding proteins in 19 significant RNA viral families, encompassing 45 viral genera and 375 viral species. The predicted metalloproteome primarily consisted of magnesium (47%) and zinc (40%) binding proteins, with manganese (11%) binding proteins also identified. Through advanced bioinformatics tools, a data set of 905 carefully selected metalloproteins underwent rigorous functional characterization. The prevalence of polyproteins (37%), RNA polymerases (22%), and proteases (10%) was observed. Furthermore, metal ion binding was achieved in viral structural, non-structural, and accessory proteins such as integrase and methyltransferase. The in-depth investigation focused on protease domains, identifying a refined set of 456 non-redundant protease domains. Among them, 78 protease domains were determined to possess metal-binding properties, with zinc and magnesium binding emphasized. The findings provide significant insights into metal-binding proteases’ distribution and evolutionary patterns, particularly in major human RNA viral proteases. Sequence similarity network analysis highlighted the presence of different classes of peptidases in viral families, such as zinc-binding peptidase C30 in the coronaviridae family, including human coronavirus proteases, and peptidase C16 in all genera of coronaviruses. This comprehensive analysis sheds light on the immense potential of metal-binding proteases as therapeutic targets. Continued exploration of metal-binding proteomes will further enhance our understanding of metal-dependent biological processes and facilitate the development of innovative antiviral strategies.

IMPORTANCE
Metal-binding proteins are pivotal components with diverse functions in organisms, including viruses. Despite their significance, many metalloproteins in viruses remain uncharacterized, posing challenges to understanding viral systems. This study addresses this knowledge gap by identifying and analyzing metal-binding proteins and proteases in RNA viruses. The findings emphasize the prevalence of these proteins as essential functional classes within viruses and shed light on the role of metal ions and metalloproteins in viral replication and pathogenesis. Moreover, this research serves as a crucial foundation for further investigations in this field, offering the potential for developing innovative antiviral strategies. Additionally, the study enhances our understanding of the distribution and evolutionary patterns of metal-binding proteases in major human viruses. Continually exploring metal-binding proteomes across diverse viruses will deepen our knowledge of metal-dependent biological processes and provide valuable insights for combating viral infections, including respiratory viruses and other life-threatening diseases.