Biosynthetic proteins targeting the SARS-CoV-2 spike as anti-virals

2022

Article référencé dans le Web of Science WOS:000892364100005

Thebault S., Lejal N., Dogliani A., Donchet A., Urvoas A., Valerio-Lepiniec M., Lavie M., Baronti Cécile, Touret F., Da Costa B., Bourgon C., Fraysse A., Saint-Albin-Deliot A., Morel J., Klonjkowski B., Lamballerie X. de, Dubuisson J., Roussel A., Minard P., Le Poder S., Meunier N., Delmas B.

PLoS Pathogens, 2022, 18 (9), p. e1010799 [21 p.] ISSN 1553-7366

The binding of the SARS-CoV-2 spike to angiotensin-converting enzyme 2 (ACE2) promotes virus entry into the cell. Targeting this interaction represents a promising strategy to generate antivirals. By screening a phage-display library of biosynthetic protein sequences build on a rigid alpha-helicoidal HEAT-like scaffold (named aReps), we selected candidates recognizing the spike receptor binding domain (RBD). Two of them (F9 and C2) bind the RBD with affinities in the nM range, displaying neutralisation activity in vitro and recognizing distinct sites, F9 overlapping the ACE2 binding motif. The F9-C2 fusion protein and a trivalent alpha Rep form (C2-foldon) display 0.1 nM affinities and EC50 of 8-18 nM for neutralization of SARS-CoV-2. In hamsters, F9-C2 instillation in the nasal cavity before or during infections effectively reduced the replication of a SARS-CoV-2 strain harbouring the D614G mutation in the nasal epithelium. Furthermore, F9-C2 and/or C2-foldon effectively neutralized SARS-CoV-2 variants (including delta and omicron variants) with EC50 values ranging from 13 to 32 nM. With their high stability and their high potency against SARS-CoV-2 variants, alpha Reps provide a promising tool for SARS-CoV-2 therapeutics to target the nasal cavity and mitigate virus dissemination in the proximal environment.

Sciences fondamentales / Techniques d'analyse et de recherche [020] ; Santé : généralités [050] ; Entomologie médicale / Parasitologie / Virologie [052]

Fonds IRD [F B010086727]

fdi:010086727