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

Ben M Flude,Andrea Brancale,Marcella Bassetto,Salvatore Ferla,Meike Heurich,Paige Mitchell,Chloe Richards,Nina Compton,Giulio Nannetti

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.

Highlights

The complement system is crucial for the activation of innate and adaptive immune responses, and it plays a key role in host defense mechanisms against pathogens [1]
MASP2 plays a central role in the lectin pathway of complement activation, as its proteolytic activity is responsible for the cleavage of the complement elements C2 into C2a, and C4 into C4b
MASP-2 represents an important target for the development of therapeutic measures to interfere with the severe consequences of infections with highly pathogenic coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2

Summary

Introduction

The complement system is crucial for the activation of innate and adaptive immune responses, and it plays a key role in host defense mechanisms against pathogens [1]. Complement may be activated through the alternative, the classical and the mannose-binding lectin (MBL) pathways. Among the three pathways of complement activation, the MBL pathway is the major player to induce a proinflammatory response in viral infections [3]. Pathogenic human viruses such as HIV (human immunodeficiency virus), SARS-CoV (severe acquired respiratory syndrome coronavirus) and Ebola virus, all directly interact with components of the MBL pathway [1], with the dysregulation of the complement system playing main roles in the pathogenesis of respiratory disorders such as acute lung injury. Acute lung injury represents the more severe form of several viral diseases, including SARS, MERS

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