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Targeting the complement serine protease MASP-2 as a therapeutic strategy for coronavirus infections

Flude, Ben M., Nannetti, Giulio, Mitchell, Paige, Compton, Nina, Richards, Chloe, Heurich, Meike, Brancale, Andrea, Ferla, Salvatore and Bassetto, Marcella 2021. Targeting the complement serine protease MASP-2 as a therapeutic strategy for coronavirus infections. Viruses 13 (2) , 312. 10.3390/v13020312

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Abstract

MASP-2, mannose-binding protein-associated serine protease 2, is a key enzyme in the lectin pathway of complement activation. Hyperactivation of this protein by human coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 has been found to contribute to aberrant complement activation in patients, leading to aggravated lung injury with potentially fatal consequences. This hyperactivation is triggered in the lungs through a conserved, direct interaction between MASP-2 and coronavirus nucleocapsid (N) proteins. Blocking this interaction with monoclonal antibodies and interfering directly with the catalytic activity of MASP-2, have been found to alleviate coronavirus-induced lung injury both in vitro and in vivo. In this study, a virtual library of 8736 licensed drugs and clinical agents has been screened in silico according to two parallel strategies. The first strategy aims at identifying direct inhibitors of MASP-2 catalytic activity, while the second strategy focusses on finding protein-protein interaction inhibitors (PPIs) of MASP-2 and coronaviral N proteins. Such agents could represent promising support treatment options to prevent lung injury and reduce mortality rates of infections caused by both present and future-emerging coronaviruses. Forty-six drug repurposing candidates were purchased and, for the ones selected as potential direct inhibitors of MASP-2, a preliminary in vitro assay was conducted to assess their interference with the lectin pathway of complement activation. Some of the tested agents displayed a dose-response inhibitory activity of the lectin pathway, potentially providing the basis for a viable support strategy to prevent the severe complications of coronavirus infections.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Additional Information: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
Publisher: MDPI
ISSN: 1999-4915
Date of First Compliant Deposit: 30 March 2021
Date of Acceptance: 15 February 2021
Last Modified: 31 Mar 2021 10:00
URI: http://orca.cf.ac.uk/id/eprint/140191

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