The ability to regulate small molecule chemistry in vivo will enable new avenues of exploration in imaging and pharmacology. However, realization of these goals will require reactions with high specificity and precise control. Here we demonstrate photocontrol over the highly specific Staudinger–Bertozzi ligation in vitro and in vivo. Our simple approach, photocaging the key phosphine atom, allows for the facile production of reagents with photochemistry that can be engineered for specific applications. The resulting compounds, which are both stable and efficiently activated, enable the spatial labeling of metabolically introduced azides in vitro and on live zebrafish.

Methods for targeting oncolytic viruses can increase efficacy and accelerate development. Genetic engineering, the predominant method for changing vector tropism, is limited in scope and often represents the bottleneck for vector development. Metabolic incorporation of an unnatural azido sugar, O-GlcNAz, at a specific site on the adenoviral surface allows chemoselective attachment of affibodies for Her2 or EGF receptors. Modification with these high-affinity, high-selectivity proteins is straightforward and readily generalizable, demonstrates minimal impact on virus physiology, and affords significant increases in gene delivery to cancer cells. As a result, this method has significant potential to increase the efficacy of next-generation viral vectors.

•N-azidoacetyl sialic acid (SiaNAz) was metabolically introduced onto viral surface.•Modification via strain-promoted click reaction yielded targeted viruses.•This novel two-step labeling method exhibited remarkable flexibility.As a result of their ability to integrate into the genome of both dividing and non-dividing cells, lentiviruses have emerged as a promising vector for gene delivery. Targeted gene transduction of specific cells and tissues by lentiviral vectors has been a major goal, which has proven difficult to achieve. We report a novel targeting protocol that relies on the chemoselective attachment of cancer specific ligands to unnatural glycans on lentiviral surfaces. This strategy exhibits minimal perturbation on virus physiology and demonstrates remarkable flexibility. It allows for targeting but can be more broadly useful with applications such as vector purification and immunomodulation.Download high-res image (232KB)Download full-size image