Page 20 - Read Online
P. 20

Page 16 of 23          Skoreński et al. Rare Dis Orphan Drugs J 2023;2:6  https://dx.doi.org/10.20517/rdodj.2022.21

               Table 2. Characterization of human neutrophil elastase inhibitors approved for use and in clinical trials
                Name         Therapeutic application            Development phase  Features
                Prolastin®   α1-antitrypsin deficiency and clinical evidence of   FDA approved  peptide reversible NE inhibitor
                         [15]
                (α1-antitrypsin)  emphysema                                      recommended dose: 60 mg/kg body
                                                                                 weight once a week (for Prolastin-C
                                                                                 Liquid)
                Elaspol®     acute lung injury and acute respiratory distress   approved for use in Japan  non-peptide competitive NE inhibitor
                (Sivelestat/   syndrome associated with the systemic inflammatory  and South Korea  IC 44 nM; K 200 nM
                                                                                  50
                                                                                          i
                ONO-5046) [35]  response syndrome
                Alvelestat   bronchiolitis obliterans syndrome  II phase clinical trials  reversible oral NE inhibitor
                       [15]
                (AZD9668)                                                        IC  12 nM; K  9.4 nM
                                                                                  50     i
                BAY 85-8501 [15]  non-cystic fibrosis bronchiectasis  II phase clinical trials  reversible NE inhibitor, IC  0.065 nM;
                                                                                                 50
                                                                                 K  0.08 nM
                                                                                  i
               NE: Neutrophil elastase.






































                                                Figure 17. Synthetic substrates of CatG.


               regarding NSP4 biology, substrate specificity and inhibitors development have been done. However, still,
               blank spots remain to be filled. NSP4, unlike other NSPs, has been conserved for over 400 million years
               from bony fish to humans . NSP4 is the only known enzyme that cleaves substrates with post-
                                        [86]
               translationally modified arginine residues, such as methylarginine and citrulline . These attributes suggest
                                                                                   [87]
               that NSP4 could have another potential function, not typical of NSPs. In 2020, AhYoung et al. demonstrated
               that NSP4 plays an essential role in mast cell biology . Their studies have shown/showed that NSP4 is
                                                              [88]
               present during early mast cell development and is critical for the regulation of levels of histamine and
               serotonin in the secretory granules of the developing mast cells. They discovered that NSP4 deficiency
               causes protection against mast cell/histamine-dependent vascular leakage. These findings open new
   15   16   17   18   19   20   21   22   23   24   25