Public Thesis defense - LIBST

Nanoscopic analysis of molecular interactions and inhibition of SARS-CoV-2 infection by Simon PETITJEAN

Pour l’obtention du grade académique de Doctorat en sciences agronomiques et ingénierie biologique

Human populations are since the dawn of time exposed to viruses, some of them causing severe diseases, as recently illustrated by the emergence of SARS-CoV-2 and the associated COVID-19 pandemic. Various strategies were developed to face the threat that viruses in general represents for human health. The most prominent is the vaccination, that despite great successes need to be complemented with antiviral drugs, including anti-adhesion strategies.

Viruses are indeed obligate intracellular parasites by nature, meaning that they cannot replicate by themselves. Consequently, they need to enter a host cell for hijacking its molecular machinery and completing their life cycle. Infection is initiated by viral attachment to the host cell membrane through biomolecular interactions between a ligand (often glycoproteins exposed at the viral surface) and its receptor (embedded in the host cell membrane), which can be studied by a plethora of technique, including force distance curves-based atomic force microscopy.

The goal of this thesis is two-fold; first, biophysically characterize these primary interactions establishing between SARS-CoV-2 spike glycoprotein and different host cell membrane components, aiming at elucidating their role at the molecular level and; secondly, test anti-adhesion molecules that could inhibit the formation of these interactions and thus infection.

Among others, we showed that SARS-CoV-2 RBD engages its main receptor ACE2 with a high affinity and proved that this interaction can be disrupted by ACE2-derived peptides. We also investigated binding to glycans, including 9-O-acetylated sialic acid (9-AcSA). Despite the moderate affinity of its engagement and its role as an attachment factor, taking advantage of the multivalent effect by building glycodendrimers presenting multiple copies of 9-AcSA allowed to create another promising SARS-CoV-2 binding and entry inhibitor. The same strategy could be applied using heparin, another glycan facilitating SARS-CoV-2 entry, in place of 9-AcSA.

Altogether, these results could contribute to the development of new antiviral therapeutics blocking viral entry, provided its further development, for example by applying some glyco-/peptidomimetics strategies.

Jury members : 

• Prof. David Alsteens (UCLouvain), supervisor
• Prof. Bernard Hallet (UCLouvain), chairperson
• Prof. Yves Dufrêne (UCLouvain), secretary
• Prof. Jacques Mahillon (UCLouvain)
• Prof. Stéphane Vincent (UNamur)
• Prof. Laurent Gillet (ULiège)

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