Characterization of human adenovirus receptors and antiviral drugs discovery

Acute respiratory infections (ARI) represent a persistent public health problem worldwide and cause significant mortality. Among respiratory viruses, human adenovirus (HAdV) is one of the most common pathogens associated with these diseases. Severe HAdV epidemics have recently occurred in the United States (New Jersey, 2018) and Asia (Vietnam, 2022), causing deaths in young children. Despite the proven clinical impact, there are no formally approved drugs by health authorities to treat these infections. The only vaccine available is for US military personnel. We therefore believe that there is an urgent need to address this unmet medical concern.

There are multiple very specific viral mechanisms for which antiviral strategies could be developed. The attachment of viruses to the host cell, an early stage of the infectious cycle, is a relevant therapeutic target.

HAdVs use their fiber protein to bind to specific surface receptors, which conditions their entire viral replication cycle. In a collaboration with our laboratory, Prof. Lieber’s group in Seattle showed that HAdV fibers with respiratory tropism bind to desmoglein-2 (DSG-2), a transmembrane protein, present in the desmosomes of many cell types (Wang et al., Nat Med 2011). Our team was able to determine by cryo-electron microscopy (cryo-EM) the structures of the complexes formed by the HAdV-3 or HAdV-7 fiber head with the extracellular domains of DSG2, allowing us to identify the critical conserved areas involved in this interaction. (Vassal-Stermann et al, Nat Com 2019 ; Hograindleur et al., Viruses 2020 )

The objective of our project is to identify small molecules able to bind in the identified areas and compete at low concentration with the binding domain of the DSG2 receptor on the fiber, in order to propose potential antiviral drugs against adenovirus infections.

In this context, we have currently started an industrial collaboration with a company aiming at testing their natural product libraries.

Collaborations :
A. Lieber, MD, PhD (Univ. Washington, USA)
K. Benihoud, Professeur (Univ. Paris-Sud, France)

Fundings :
Contrat de collaboration industrielle CNRS/ SILAB (N°251299).

Communications :
Les defis du CEA 231 Octobre 2018 (p8)
IBS Actualités n°54 Mars 2019 (p2)
INSB Actualités Mars 2019
ESRF Spotlight on Science