Double functionalized Sindbis E2 glycoprotein modifies Sindbis tropism favouring infection of α5β1⁺ glioblastoma cells.

Effective cancer therapy hinges on the ability to selectively target malignant cells while sparing healthy tissues. For virotherapy this goal can be achieved by genetic engineering the surface glycoproteins of viruses. This approach, though, often leads to loss of functionality of the engineered proteins, in terms of membrane fusion. Here, we modified the E2 protein of Sindbis virus, preserving the ability of transduction by lentivectors pseudotyped by the Sindbis Env proteins. The modifications introduced allowed to alter the efficiency of transduction of glioblastoma cells expressing integrin α5β1, a driver of resistance to treatments and frequently associated to recurrences. Importantly, the same modifications of E2 also conferred, to a replication-competent Sindbis strain, the ability to kill preferentially α5β1⁺ over α5β1⁻ glioblastoma cells in culture. Finally, the same strain reduced the expansion of α5β1⁺ glioblastoma cancers in the brain of immunodeficient mice when injected in the tail vein.