Inhibition of influenza virus infection and hemagglutinin cleavage by the protease inhibitor HAI-2

Abstract

Influenza virus remains a significant concern to public health, with the continued potential for a high fatality pandemic. Vaccination and antiviral therapeutics are effective measures to circumvent influenza virus infection, however, multiple strains have emerged that are resistant to the antiviral therapeutics currently on the market. With this considered, investigation of alternative antiviral therapeutics is being conducted. One such approach is to inhibit cleavage activation of the influenza virus hemagglutinin (HA), which is an essential step in the viral replication cycle that permits viral-endosome fusion. Therefore, targeting trypsin-like, host proteases responsible for HA cleavage in vivo may prove to be an effective therapeutic. Hepatocyte growth factor activator inhibitor 2 (HAI-2) is naturally expressed in the respiratory tract and is a potent inhibitor of trypsin-like serine proteases, some of which have been determined to cleave HA. In this study, we demonstrate that HAI-2 is an effective inhibitor of cleavage of HA from the human-adapted H1 and H3 subtypes. HAI-2 inhibited influenza virus H1N1 infection in cell culture, and HAI-2 administration showed protection in a mouse model of influenza. HAI-2 has the potential to be an effective, alternative antiviral therapeutic for influenza.

TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections

“…In addition, hepatocyte growth factor activator inhibitor 2 (HAI-2, PDB ID: 3Q02) has been reported to efficiently inhibit HA-cleaving proteases such as TMPRSS2 and TMPRSS4 [64]. HAI-2 has also been shown to inhibit H1N1 influenza virus (A/PR/8/34) infection in vitro and to protect animals from H1N1 influenza virus (A/PR/8/34) infections in a mouse model [79]. These results suggest that localized administration of PAI-1 or HAI-2 in the respiratory tract might be a new therapeutic approach for the treatment of influenza virus, coronavirus or other respiratory virus infections that require host protease-driven maturation.…”

SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses

“…However, when targeting host specific factors there are potential off target effects, and therefore the potential side effects of targeting host proteases requires further investigation. Hamilton et al reported that the hepatocyte growth activator inhibitor 2 (HAI-2) effectively inhibited trypsinmediated cleavage of H1N1 and H3N2 in vitro and in vivo (Hamilton et al, 2014). HAI-2 is encoded by the SPINT2 gene; hereafter we will also refer to the protein as SPINT2.…”

Human matriptase/ST 14 proteolytically cleaves H7N9 hemagglutinin and facilitates the activation of influenza A/Shanghai/2/2013 virus in cell culture

“…This is well‐illustrated by the finding that H7N9 viruses from the 5th wave were antigenically distinct from the viruses that emerged in 2013, rendering existing candidate vaccines ineffective . Novel approaches to fight influenza infections include targeting host proteases that are responsible for the activation of the virus . A major benefit of this approach is that it is very unlikely to lead to resistance phenotypes in the virus.…”