Type II transmembrane serine proteases as potential target for anti-influenza drug discovery

ABSTRACT

Introduction: The outbreak of an influenza pandemic as well as the continued circulation of seasonal influenza highlights the need for effective antiviral therapies. The emergence of drug-resistant strains further necessitates the development of novel antivirals that target the host factors crucial for viral replication.

Area covered: This review summarizes the current understanding of the structural and functional properties of type II transmembrane serine proteases (TTSPs) as a proteolytic activator of influenza virus infection and discusses their potential as antiviral targets. It also explores the experimental evidence accumulated for inhibitors of TTSPs as novel, broad-spectrum antivirals against various influenza virus subtypes. The review also provides an overview of the properties of small molecules, proteins, and peptides that efficiently inhibit the proteolytic activation of the influenza virus.

Expert opinion: TTSPs activate a wide range of influenza virus subtypes including avian influenza viruses, both in vitro and in vivo, via proteolytic cleavage of influenza hemagglutinin (HA) into infection-competent fusogenic conformation. Other viruses such as SARS-, MERS-coronaviruses and human metapneumoviruses may use the same host cell proteases for activation, implying that TTSP inhibition might be a novel strategy for developing broad-spectrum antiviral agents for respiratory viral infections.

KEYWORDS:

• Influenza virus
• type II transmembrane serine protease
• novel antiviral target
• drug discovery
• antiviral

Article highlights

• The recent outbreak of highly pathogenic avian influenza virus and H1N1 swine-origin influenza virus, as well as the emergence of antiviral resistant strains calls for the discovery of novel antivirals and antiviral target against influenza infections.

• Progresses have been made in antiviral drug development against new targets including viral polymerase complex, viral NS1 protein and nucleoprotein.

• Members of type II transmembrane serine proteases (TTSPs) activate a wide range of influenza virus subtypes including avian influenza viruses via proteolytic cleavage of influenza hemagglutinin (HA) into infection-competent fusogenic conformation.

• Tmprss2-/-, Tmprss4-/- double-knockout mice show reduced body weight loss and mortality after infection with influenza A virus.

• TTSPs inhibition may serve as a novel strategy for developing broad-spectrum antiviral agents against viruses share the similar proteolytic activation function such as influenza, SARS-, MERS-coronaviruses and human metapneumoviruses Viruses.

This box summarizes key points contained in the article.

Acknowledgments

The authors gratefully acknowledge the language editing support from Hannah Seong of the New York University and Redeemer Presbyterian Church, New York.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors are supported by grants from the Ministry of Health and Welfare (A103001 and HI13C0826) and the Ministry of Agriculture, Food and Rural Affairs (MAFRA 716002-7) from the Korean Government and the National Research Foundation of Korea (NRF-2016R1A5A2012284).