Biology subjects

Declerck, P.

Publications and source records attributed to Declerck, P..

3 recordsLinked to original sources

bioRxiv2022

Identification of a phage display-derived peptide interacting with the N-terminal region of Factor VII activating protease (FSAP) enables characterization of zymogen activation.

Increased Factor VII activating protease (FSAP) activity has a protective effect in diverse disease conditions as inferred from studies in FSAP-/- mice and humans deficient in FSAP activity due to a single nucleotide polymorphism. The activation of FSAP zymogen in plasma is mediated by extracellular histones that are released during tissue injury or inflammation or by positively charged surfaces. However, it is not clear if this activation mechanism is specific and amenable to manipulation. Using a phage display approach we have identified a peptide, NNKC9/41, that activates pro-FSAP in plasma. Other commonly found zymogens in the plasma were not activated. Binding studies with FSAP domain deletion mutants indicate that the N-terminus of FSAP is the key interaction site of this peptide. Blocking the contact pathway of coagulation did not influence pro-FSAP activation by the peptide. In a monoclonal antibody screen, we identified MA-FSAP-38C7 that prevented the activation of pro-FSAP by the peptide. This antibody bound to the LESLDP sequence (amino acids 30-35) in the N-terminus of FSAP. The plasma clotting time was shortened by NNKC9/41 and this was reversed by MA-FSAP-38C7 demonstrating the utility of this peptide. Identification of this peptide, and the corresponding interaction site, provides proof of principle that it is possible to activate a single protease zymogen in blood in a specific manner. Peptide NNKC/41 will be useful as a tool to delineate the molecular mechanism of activation of pro-FSAP in more detail, elucidate its biological role. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/475526v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@112eea6org.highwire.dtl.DTLVardef@1f1d7eaorg.highwire.dtl.DTLVardef@967b03org.highwire.dtl.DTLVardef@1662c51_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2021

Anti-SARS-CoV-2 human antibodies retaining neutralizing activity against SARS-CoV-2 B.1.1.529 (omicron)

SARS-CoV-2 B.1.1.529, designated omicron, was recently identified as a new variant of concern by WHO and is rapidly replacing SARS-CoV-2 delta as the most dominant variant in many countries. Unfortunately, because of the high number of mutations present in the spike of SARS-CoV-2 omicron, most monoclonal antibodies (mAbs) currently approved for treatment of COVID-19 lose their in vitro neutralizing activity against this variant. We recently described a panel of human anti-SARS-CoV-2 mAbs that potently neutralize SARS-CoV-2 Wuhan, D614G and variants alpha, beta, gamma and delta. In this work, we evaluated our mAb panel for potential in vitro activity against SARS-CoV-2 delta and omicron. Three mAbs from our panel retain neutralizing activity against both delta and omicron, with mAb 3B8 still resulting in complete neutralization at a concentration as low as 0.02 g/ml for both variants. Overall, our data indicate that mAb 3B8 may have the potential to become a game-changer in the fight against the continuously evolving SARS-CoV-2.

immunology↗

bioRxiv2021

Potent neutralizing anti-SARS-CoV-2 human antibodies cure infection with SARS-CoV-2 variants in hamster model

Treatment with neutralizing monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributes to COVID-19 management. Unfortunately, SARS-CoV-2 variants can escape several of these recently approved mAbs, highlighting the need for additional discovery and development. In a convalescent COVID-19 patient, we identified six mAbs, classified in four epitope groups, that potently neutralized SARS-CoV-2 Wuhan, alpha, beta, gamma and delta infection in vitro. In hamsters, mAbs 3E6 and 3B8 potently cured infection with SARS-CoV-2 Wuhan, beta and delta when administered post-viral infection at 5 mg/kg. Even at 0.2 mg/kg, 3B8 still reduced viral titers. Intramuscular delivery of DNA-encoded 3B8 resulted in in vivo mAb production of median serum levels up to 90 g/ml, and protected hamsters against delta infection. Overall, our data mark 3B8 as a promising candidate against COVID-19, and highlight advances in both the identification and gene-based delivery of potent human mAbs.

immunology↗