Protease-Specific Biomarkers to Analyse Protease Inhibitors for Emphysema Associated with Alpha 1-Antitrypsin Deficiency. An Overview of Current Approaches

Int J Mol Sci. 2021 Jan 21;22(3):1065. doi: 10.3390/ijms22031065.

Abstract

As a known genetic cause of chronic obstructive pulmonary disease (COPD), alpha1-antitrypsin deficiency (AATD) can cause severe respiratory problems at a relatively young age. These problems are caused by decreased or absent levels of alpha1-antitrypsin (AAT), an antiprotease which is primarily functional in the respiratory system. If the levels of AAT fall below the protective threshold of 11 µM, the neutrophil-derived serine proteases neutrophil elastase (NE) and proteinase 3 (PR3), which are targets of AAT, are not sufficiently inhibited, resulting in excessive degradation of the lung parenchyma, increased inflammation, and increased susceptibility to infections. Because other therapies are still in the early phases of development, the only therapy currently available for AATD is AAT augmentation therapy. The controversy surrounding AAT augmentation therapy concerns its efficiency, as protection of lung function decline is not demonstrated, despite the treatment's proven significant effect on lung density change in the long term. In this review article, novel biomarkers of NE and PR3 activity and their use to assess the efficacy of AAT augmentation therapy are discussed. Furthermore, a series of seven synthetic NE and PR3 inhibitors that can be used to evaluate the specificity of the novel biomarkers, and with potential as new drugs, are discussed.

Keywords: AAT; AAT replacement therapy; AATD; alpha1-antitrypsin; alpha1-antitrypsin deficiency; human neutrophil elastase; proteinase 3; synthetic NE inhibitors; synthetic proteinase 3 inhibitors.

Publication types

  • Review

MeSH terms

  • Animals
  • Biomarkers*
  • Disease Management
  • Disease Susceptibility
  • Drug Discovery / methods
  • Humans
  • Peptide Hydrolases / chemistry
  • Peptide Hydrolases / metabolism*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / therapeutic use
  • Pulmonary Emphysema / diagnosis
  • Pulmonary Emphysema / drug therapy
  • Pulmonary Emphysema / etiology*
  • Pulmonary Emphysema / metabolism*
  • Structure-Activity Relationship
  • alpha 1-Antitrypsin Deficiency / complications*

Substances

  • Biomarkers
  • Protease Inhibitors
  • Peptide Hydrolases