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The Antiviral Potential of Host Protease Inhibitors

  • Torsten Steinmetzer
  • Kornelia Hardes
Chapter

Abstract

The replication of numerous pathogenic viruses depends on host proteases, which therefore emerged as potential antiviral drug targets. In some cases, e.g., for influenza viruses, their function during the viral propagation cycle is relatively well understood, where they cleave and activate viral surface glycoproteins. For other viruses, e.g., Ebola virus, the function of host proteases during replication is still not clear. Host proteases may also contribute to the pathogenicity of virus infection by activating proinflammatory cytokines. For some coronaviruses, human proteases can also serve in a nonproteolytical fashion simply as receptors for virus entry. However, blocking of such protein-protein contacts is challenging, because receptor surfaces are often flat and difficult to address with small molecules. In contrast, many proteases possess well-defined binding pockets. Therefore, they can be considered as well-druggable targets, especially, if they are extracellularly active. The number of their experimental crystal structures is steadily increasing, which is an important prerequisite for a rational structure-based inhibitor design using computational chemistry tools in combination with classical medicinal chemistry approaches. Moreover, host proteases can be considered as stable targets, and their inhibition should prevent rapid resistance developments, which is often observed when addressing viral proteins. Otherwise, the inhibition of host proteases can also affect normal physiological processes leading to a higher probability of side effects and a narrow therapeutic window. Therefore, they should be preferably used in combination therapies with additional antiviral drugs. This strategy should provide a stronger antiviral efficacy, allow to use lower drug doses, and minimize side effects. Despite numerous experimental findings on their antiviral activity, no small-molecule inhibitors of host proteases have been approved for the treatment of virus infections, so far.

Keywords

Antiviral drugs Protease inhibitors Host targets Serine proteases Structure-based drug design 

Abbreviations

Agm

Agmatine

BBI

Bowman-Birk inhibitor

CCHFV

Crimean-Congo hemorrhagic fever virus

CMK

Chloromethyl ketone

Dec

Decanoyl

EboV

Ebola virus

GP

Glycoprotein

HA

Hemagglutinin

HAT

Human airway trypsin-like peptidase

HIV

Human immunodeficiency virus

HPAIV

Highly pathogenic avian influenza virus

HPIV

Human parainfluenza virus

hTyr

Homotyrosin

IAV

Influenza A virus

IBV

Influenza B virus

LASV

Lassa virus

LBS

Lysine binding site

LCMV

Lymphocytic choriomeningitis virus

LPAIV

Low pathogenic avian influenza virus

MERS-CoV

Middle East respiratory syndrome coronavirus

PAR-2

Protease-activated receptor 2

PC

Proprotein convertase

Phac

Phenylacetyl

PPI

Protein-protein interaction

SARS-CoV

Severe acute respiratory syndrome coronavirus

S-protein

Spike protein

TLSP

Trypsin-like serine protease

TTSP

Type II transmembrane serine protease

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Pharmaceutical ChemistryPhilipps UniversityMarburgGermany

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