Article ; Online: Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections.
2021 Volume 13, Issue 2
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 ... ...
| 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. |
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| MeSH term(s) | Coronavirus Infections/drug therapy ; Coronavirus Nucleocapsid Proteins/antagonists & inhibitors ; Coronavirus Nucleocapsid Proteins/metabolism ; Drug Repositioning ; Enzyme Inhibitors/chemistry ; Humans ; Mannose-Binding Protein-Associated Serine Proteases/metabolism ; Protein Binding/drug effects ; Structure-Activity Relationship |
| Chemical Substances | Coronavirus Nucleocapsid Proteins ; Enzyme Inhibitors ; MASP2 protein, human (EC 3.4.21.-) ; Mannose-Binding Protein-Associated Serine Proteases (EC 3.4.21.-) |
| Language | English |
| Publishing date | 2021-02-17 |
| Publishing country | Switzerland |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2516098-9 |
| ISSN | 1999-4915 ; 1999-4915 |
| ISSN (online) | 1999-4915 |
| ISSN | 1999-4915 |
| DOI | 10.3390/v13020312 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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