Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections
| Autor: | Andrea Brancale, Ben Matthew Flude, Giulio Nannetti, Meike Heurich, Salvatore Ferla, Nina Compton, Chloe Richards, Marcella Bassetto, Paige Mitchell |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.drug_class In silico coronaviruses lcsh:QR1-502 Lung injury medicine.disease_cause Monoclonal antibody lcsh:Microbiology Article Microbiology Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Virology Coronavirus Nucleocapsid Proteins Humans Medicine Enzyme Inhibitors Coronavirus Serine protease biology drug repurposing business.industry Drug Repositioning MASP-2 Complement system molecular modelling Drug repositioning 030104 developmental biology Infectious Diseases Mannose-Binding Protein-Associated Serine Proteases 030220 oncology & carcinogenesis Lectin pathway biology.protein Coronavirus Infections business Protein Binding |
| Zdroj: | Viruses Volume 13 Issue 2 Viruses, Vol 13, Iss 312, p 312 (2021) |
| ISSN: | 1999-4915 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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