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Page 10 of 23 Skoreński et al. Rare Dis Orphan Drugs J 2023;2:6 https://dx.doi.org/10.20517/rdodj.2022.21
Figure 11. Structures of natural cyclodepsipeptide-type HNE inhibitors [48] .
Overexpression of PR3 can be associated with the development of autonomous cell growth in leukemia. PR3
also plays a major role as an autoantigen in many diseases, including granulomatosis with polyangiitis
(GPA) and idiopathic interstitial pneumonia, and is also a target of anti-neutrophil cytoplasmic antibodies
(ANCA) in vasculitis. In physiological conditions, the PR3 activity is regulated by natural inhibitors,
including serpins (α PI, monocyte neutrophil elastase inhibitor), chelonians (elafin, secretory leukocyte
1
protease inhibitor), and α2-macroglobulin [54,55,57] .
PR3 Synthetic substrates
For a long time, a synthesis of selective substrate for PR3 was difficult, mainly due to it being closely related
to HNE and having a similar preference for small aliphatic amino acid residues at P1. In 2012, Epinette et
al. published a new structure of selective FRET-type peptide substrate for PR3 without activity towards
other serine proteases, especially HNE, ABZ-Val-Ala-Asp-norVal-Ala-Asp-Tyr-Gln-EDDnp with a K
M
value of 1.2 µM . Another structure of selective FRET-type PR3 substrate consists of ABZ and Tyr(3-NO )
[58]
2
