Chemoselective modification of viral proteins bearing metabolically introduced
Banerjee PS, Carrico IS. Methods Mol Biol,
The inherent difficulty of performing chemical modifications of proteins in a truly site-specific fashion is often compounded by the need to work within complex biological settings. In order to alleviate this complication, targets can be "prelabeled" metabolically with unnatural residues, which allow access to highly selective bioorthogonal reactions. Due to their small size, permissibility within biosynthetic pathways and access to reactions with high specificity, azides provide excellent bioorthogonal handles. This two-step labeling process is emerging as a highly effective means to modify therapeutic proteins. In this chapter, we take this strategy a step further and apply chemoselective ligation to remodel the surfaces of adenoviruses. Despite the large number of ongoing clinical trials involving these complex mammalian viruses, new methods for their facile, flexible surface modification are necessary to drive the development of next-generation therapeutics. Here we demonstrate the modification of azides on adenoviral surfaces via a straightforward chemoselective protocol based on copper-assisted "click" chemistry. This method provides access to a wide array of effector functionalities without sacrificing infectivity.