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Article

Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections

1
Department of Chemistry, College of Science and Engineering, Swansea University, Swansea SA28PP, UK
2
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK
3
Crosskeys Campus, Coleg Gwent, Crosskeys NP117ZA, UK
4
Ysgol Gyfun Rhydywaun, Rhondda Cynon Taf CF449ES, UK
5
Swansea University Medical School, Swansea SA28PP, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Graciela Andrei
Received: 14 January 2021 / Revised: 9 February 2021 / Accepted: 15 February 2021 / Published: 17 February 2021
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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. View Full-Text
Keywords: MASP-2; coronaviruses; molecular modelling; drug repurposing MASP-2; coronaviruses; molecular modelling; drug repurposing
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MDPI and ACS Style

Flude, B.M.; Nannetti, G.; Mitchell, P.; Compton, N.; Richards, C.; Heurich, M.; Brancale, A.; Ferla, S.; Bassetto, M. Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections. Viruses 2021, 13, 312. https://0-doi-org.brum.beds.ac.uk/10.3390/v13020312

AMA Style

Flude BM, Nannetti G, Mitchell P, Compton N, Richards C, Heurich M, Brancale A, Ferla S, Bassetto M. Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections. Viruses. 2021; 13(2):312. https://0-doi-org.brum.beds.ac.uk/10.3390/v13020312

Chicago/Turabian Style

Flude, Ben M., Giulio Nannetti, Paige Mitchell, Nina Compton, Chloe Richards, Meike Heurich, Andrea Brancale, Salvatore Ferla, and Marcella Bassetto. 2021. "Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections" Viruses 13, no. 2: 312. https://0-doi-org.brum.beds.ac.uk/10.3390/v13020312

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