Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections.
Viruses
; 13(2)2021 02 17.
Article
in English
| MEDLINE | ID: covidwho-1122299
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.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Protein Binding
/
Enzyme Inhibitors
/
Mannose-Binding Protein-Associated Serine Proteases
/
Coronavirus Nucleocapsid Proteins
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Year:
2021
Document Type:
Article
Affiliation country:
V13020312
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