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Institut de Biologie StructuraleGrenoble / France

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Presentation of the Fender’s team

Members
Team Leader : Pascal Fender (DR2-CNRS)

Team Members :
- Emilie Stermann (IR2-CNRS)
- Charles Vragniau (Thésard-UGA)
- Manon Mottet (M2-Labex Gral)

Adenovirus and therapeutic applications

Adenoviruses are non-enveloped, linear double-stranded DNA viruses that affect many species. In humans sixty serotypes have been identified so far causing mild diseases in healthy people, such as conjunctivitis, pneunomia or gastroenteritis.

The icosahedral capsid is made of three major capsid proteins

- The fiber (recognizing the attachment receptor)
- The penton base (triggering endocytosis mediated by integrins)
- The hexon (facets component of the capsid capable of interacting with blood factors such as FIX or FX)

Of note, Adenoviruses are the most used vector in Human gene therapy trials. Their success is primarily based on the development of oncolytic adenovirus capable of specifically lysing tumors. These viruses are already approved in Humans in some countries and the FDA would soon approve the US.

Discoveries and team goals

The team has been created in 2014 from a solid experience in the study of the viral capsid proteins and particularly on the study of an atypical virus-like particle particle composed of the symmetrical assemble of twelve penton bases with twelve fibers projected outwards : the dodecahedron. This particle has alternately been characterized from a functional point of view, from a structural point of view, has served as a tool to fish the adenovirus receptor and recently, its biological role in the viral cycle has been demonstrated. Indeed, this particle produced in excess during the viral replication triggers a remodeling of the cells that allows the virus to spread in tissues (Lu et al., PLoS Path 2013). In a partnership (NIH Consortium) with Professor Lieber in Seattle, we have identified that Desmoglein 2 (DSG2) was the receptor for subgroup B adenoviruses (Wang et al., Nat Med 2011). We have also shown that dodecahedrons by causing cellular remodeling could also act as an adjuvant to already approved treatments for cancer such as Herceptin or Doxil (Richter et al., Mol Ther 2015).


Figure : Integrative Biology : from virus to applications. The "Adenovirus" team starts from adenovirus or dodecahedron structure to identify receptors, then characterizes these interactions at the biochemical or cellular level and eventually develop new therapeutic approaches.

The objectives for the coming years are to solve the structure of the fiber in complex to DSG2 with the aim to rationally design the next generation of retargeted oncolytic adenoviruses. For this, we will biochemically map the DSG2 minimal essential domain required for this interaction and co-crystallize it with the fiber Knob domain. The second goal of the team is to develop new therapeutic approaches using dodecahedrons not only as a therapeutic adjuvant but also as a direct therapeutic vector.

Key words
Molecular and structural virology, molecular and structural oncology, host-pathogen interaction.

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