Cellular binding of a virus developed in cancer therapy elucidated at the atomic level

Adenoviruses cause diseases that can sometimes be fatal. By modifying them, they can also become formidable cancer cell killers. Adenoviruses are to date the most commonly used vectors in human clinical trials. Researchers have just elucidated by cryo electron microscopy the mechanism by which adenoviruses attach themselves to the cell surface. These results, published in the journal Nature Communication on March 12, 2019, could pave the way for the development of new generation anti-tumor vectors.

More than 60 adenovirus (Ad) serotypes are known in humans. While they are able to cause different types of diseases such as gastroenteritis or conjunctivitis, most of them have respiratory tropism. From childhood or adolescence, we have all been infected with several adenovirus serotypes either symptomatically (pneunomia, pharyngitis) or sometimes asymptomatically. Although not strictly speaking a major public health problem, several serotypes such as Ad3, Ad7 Ad11 and Ad14 (the subject of this study) may have been responsible for deaths among military recruits in the United States or more recently in a rehabilitation center in New Jersey where 11 of the 35 young patients died of Ad7 infection in late 2018.
In addition to this pathogenicity, adenoviruses are the most commonly used vectors in human clinical trials. Their success lies essentially in their use as oncolytic viruses. To do this, adenoviruses are modified to replicate only in the cancer cells. This treatment is already approved in China for some indications and numerous clinical trials are underway in the United States and Europe, offering great hope for new anti-tumor strategies.
Any virus needs to enter a cell to replicate, so binding to receptors on the cell surface is a key step in infection. It had been shown that some adenoviruses (Ad3, Ad7, Ad11 and Ad14) used desmoglein 2 (DSG2) to bind and enter cells. It remained to be understood at the molecular level how the adenovirus fibre (an elongated antenna-like protein present at 12 copies per virus) interacted with DSG2.
Until recently, solving the atomic structure of a small complex (the fiber/DSG2 complex is only 96kDa) seemed unthinkable. The latest technological developments of the Krios microscope have shown that this barrier can be broken. The researchers solved the structure of this complex at the atomic scale and visualized both the fibre and DSG2 residues that are involved in the interaction. Moreover, they showed that a point mutation in a single amino acid in adenoviruses was sufficient to completely abolish its binding to this receptor.
Understanding the mechanisms of adenovirus attachment to DSG2 opens two perspectives: on the one hand, consider the rational design of inhibitors of these pathogenic viruses and on the other hand, improve the targeting of oncolytic adenoviruses to tumors.

Cryo-EM structure of adenovirus type 3 fibre with desmoglein 2 shows an unsual mode of receptor engagement. Vassal-Stermann E, Effantin G, Zubieta C, Burmeister W, Iséni F, Wang H, Lieber A, Schoehn G, Fender P. Nature Communications in press, (2019)