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

Flude, Ben M., Nannetti, Giulio ORCID: https://orcid.org/0000-0003-3227-1537, Mitchell, Paige, Compton, Nina, Richards, Chloe, Heurich, Meike ORCID: https://orcid.org/0000-0003-0105-2702, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Ferla, Salvatore ORCID: https://orcid.org/0000-0002-5918-9237 and Bassetto, Marcella ORCID: https://orcid.org/0000-0002-2491-5868 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:	27 Mar 2024 07:33
URI:	https://orca.cardiff.ac.uk/id/eprint/140191

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