Journal Article

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

Saint-Albin-Deliot, Audrey, Virologie UMR1161 (VIRO) ; École nationale vétérinaire d'Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie ; Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Le Poder, Sophie, Minard, Philippe, Baronti, Cécile, Urvoas, Agathe, Lejal, Nathalie, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL) ; Institut Pasteur de Lille ; Pasteur Network (Réseau International des Instituts Pasteur)-Pasteur Network (Réseau International des Instituts Pasteur)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [CHU Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Virologie et Immunolo

2022

Overview

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 αReps), 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 αRep form (C2-foldon) display 0.1 nM affinities and EC 50 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 EC 50 values ranging from 13 to 32 nM. With their high stability and their high potency against SARS-CoV-2 variants, αReps provide a promising tool for SARS-CoV-2 therapeutics to target the nasal cavity and mitigate virus dissemination in the proximal environment.

• Publisher: CCSD,Public Library of Science,Public Library of Science (PLoS)
• Subject: ACE2 / Affinity / Amino acids / Angiotensin / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - chemistry / Angiotensin-Converting Enzyme 2 - metabolism / Antibodies / Antiviral agents / Antiviral Agents - chemistry / Antiviral Agents - pharmacology / Antiviral drugs / Binding / Binding sites / Biology and life sciences / Cloning / Coronaviruses / COVID-19 / COVID-19 Drug Treatment / Disease transmission / Enzyme binding / Epithelium / Fusion protein / Hamsters / Health aspects / Humans / Infections / Influenza / Interferometry / Life Sciences / Ligands / Medicine and health sciences / Microbiology and Parasitology / Mutation / Neutralization / Nose / Pandemics / Peptidyl-dipeptidase A / Peptidyl-Dipeptidase A - metabolism / Phages / Product development / Prokaryotes / Protein Binding / Protein structure / Proteins / Recombinant Fusion Proteins - pharmacology / Recombinant Fusion Proteins - therapeutic use / Recombinant Proteins - pharmacology / Recombinant Proteins - therapeutic use / Research and Analysis Methods / SARS-CoV-2 - genetics / Severe acute respiratory syndrome / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus - metabolism / Virology / Viruses
• ISBN: 0008923641000