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

Viruses. 2021 Feb 17;13(2):312. doi: 10.3390/v13020312.

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: MASP-2; coronaviruses; drug repurposing; molecular modelling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Coronavirus Nucleocapsid Proteins
  • Enzyme Inhibitors
  • MASP2 protein, human
  • Mannose-Binding Protein-Associated Serine Proteases