About: Highly potent anti-SARS-CoV-2 multi-DARPin therapeutic candidates

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About: Highly potent anti-SARS-CoV-2 multi-DARPin therapeutic candidates Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	Highly potent anti-SARS-CoV-2 multi-DARPin therapeutic candidates
Creator	Bosch, Berend-Jan Li, Wentao Wang, Chunyan Engler, Olivier Lehmann, Andreas Mangold, Susanne Franchini, Marco Lyoo, Heyrhyoung Stittelaar, Koert Van Kuppeveld, Frank De Waal, Leon Drulyte, Ieva Hurdiss, Daniel Dawson, Keith Paladino, Maria Stumpp, Michael Bosshart, Andreas Calabro, Valérie Cornelius, Andreas Fontaine, Simon Haeuptle, Micha Herzog, Christel Hospodarsch, Tanja Hänggi, Martin Iss, Chloe Kaspar Binz, H Kaufmann, Yvonne Lewis, Seth Loser, Thamar Matzner, Mirela Mayor, Jennifer Neculcea, Alexandra Proba, Karl Radom, Filip Reichen, Christian Rothenberger, Sylvia Ryter, Sarah Schildknecht, Patricia Schlegel, Anja Schlegel, Iris Sigrist, Gabriel Steiner, Daniel Straumann, Marcel Vagt, Toni Veitonmäki, Niina Villemagne, Denis Walser, Marcel Zitt, Christof Zürcher, Alexander
source	BioRxiv
abstract	Globally accessible preventive and therapeutic molecules against SARS-CoV-2 are urgently needed. DARPin molecules are an emerging class of novel therapeutics based on naturally occurring repeat proteins (∼15 kDa in size) and can be rapidly produced in bacteria in large quantities. Here, we report the identification of 380 DARPin molecules specifically targeting the SARS-CoV-2 spike protein selected from a naïve library of 1012 DARPin molecules. Using extensive biophysical and biochemical characterization, (pseudo)virus neutralization assays and cryo-EM analysis, 11 mono-DARPin molecules targeting either the receptor binding domain (RBD), the S1 N-terminal-domain (NTD) or the S2 domain of the SARS-CoV-2 spike protein were chosen. Based on these 11 mono-DARPin molecules, 31 anti-SARS-CoV-2 multi-DARPin molecules were constructed which can broadly be grouped into 2 types; multi-paratopic RBD-neutralizing DARPin molecules and multi-mode DARPin molecules targeting simultaneously RBD, NTD and the S2 domain. Each of these multi-DARPin molecules acts by binding with 3 DARPin modules to the SARS-CoV-2 spike protein, leading to potent inhibition of SARS-CoV-2 infection down to 1 ng/ml (12 pM) and potentially providing protection against viral escape mutations. Additionally, 2 DARPin modules binding serum albumin, conferring an expected half-life of about 3 weeks in humans, were included in the multi-DARPin molecules. The protective efficacy of one multi-DARPin molecule was studied in a Golden Syrian hamster SARS-CoV-2 infection model, resulting in a significant reduction in viral load and pathogenesis. In conclusion, the multi-DARPin molecules reported here display very high antiviral potency, high-production yield, and a long systemic half-life, and thereby have the potential for single-dose use for prevention and treatment of COVID-19.
has issue date	2020-08-26(xsd:dateTime)
bibo:doi	10.1101/2020.08.25.256339
has license	biorxiv
sha1sum (hex)	4e736493a33e220ae09d5cbbbc918f09e0a2d72a
schema:url	https://doi.org/10.1101/2020.08.25.256339
resource representing a document's title	Highly potent anti-SARS-CoV-2 multi-DARPin therapeutic candidates
schema:publication	bioRxiv
resource representing a document's body	covid:4e736493a33e220ae09d5cbbbc918f09e0a2d72a#body_text
is schema:about of	named entity 'molecules' named entity 'SARS-CoV-2' named entity 'circular dichroism' named entity 'spike protein' named entity 'COVID' named entity 'molecule' named entity 'RBD' named entity 'DARPin' named entity 'virus' named entity 'peptide' named entity 'HSA' named entity 'antibodies' named entity 'virus' named entity 'ACE2' named entity 'SARS-CoV-2' named entity 'DARPin' named entity 'Virology' named entity 'ectodomain' named entity 'spike protein' named entity 'Structural analysis' named entity 'interact' named entity 'IC50' named entity 'NTD' named entity 'Vero E6' named entity 'epitope' named entity 'ankyrin repeats' named entity 'surface plasmon resonance' named entity 'binding affinities' named entity 'MRE' named entity 'interface area' named entity 'SDS-PAGE' named entity 'tissue sections' named entity 'viruses' named entity 'RBD' named entity 'RBD' named entity 'DARPin'

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