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Skoreński et al. Rare Dis Orphan Drugs J 2023;2:6 https://dx.doi.org/10.20517/rdodj.2022.21 Page 5 of 23

obliterans syndrome (BOS). Compound BAY 85-8501 (3) is a selective, reversible HNE inhibitor, with IC
50
[15]
of 0.065 nM, and is also currently in phase II of clinical trials to treat bronchiectasis [Figure 3].
Peptides chloromethyl ketone (CMK) are well-known inhibitors of HNE, with the most effective MeO-Suc-
-1 -1[36]
Ala-Ala-Pro-Val-CMK (4) with a k /[I] value of 922 M s [Figure 4]. This group of inhibitors was useful
obs
for HNE structural studies and still serves as a cross-referent for newly developed HNE inhibitors. However,
peptide-CMK has not been used in any clinical trials or therapy due to its high reactivity and potential
toxicity .
[37]

Compounds belonging to a group of diaryl esters of 1-aminoalkylphosphonate are well-known as highly
selective and specific irreversible inhibitors of several serine proteases including NSPs. Compound 61 (5) is
a peptide derivative of diaryl ester of 1-aminoalkylphosphonate [Figure 5], named 2-(4-(2-((S)-1-((S)-2-((R)
-1-(Bis(4-(methylthio)phenoxy)-phosphoryl)-2-methylpropylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-
oxobutan-2-ylamino)-2-oxoethoxy)phenoxy)acetic acid, and is an example of an irreversible and selective
inhibitor of HNE with k /K of 2,353,000 ± 89,000 M s . This group of inhibitors shows great stability in
-1 -1
inact
I
human plasma and PBS. The stability of irreversible interaction at elastase-inhibitor (compound 61)
complex in time was confirmed; after 50 days of incubation, HNE recovered only 15% of initial activity .
[38]
Diazaborines represent a new class of inhibitors of serine proteases with boron-based (B-N) heterocycle
warheads, which can be used as a boronic acid replacement with similar activity and selectivity but better
stability in plasma. This group has been described as reversible covalent inhibitors with selectivity toward
HNE, and without activity against urokinase, trypsin, thrombin, kallikrein, and chymotrypsin. Cytotoxicity
assay based on a human cell line HEK 293T confirms non-toxicity of diazaborines in concentrations of up
to 100 µM after 48 h of incubation. The best results were obtained for the N-p-toluenesulfonyl substituent
[39]
compound 18 (6) (IC = 2.7 ± 0.6 µM) and compound 19 (7) (IC = 0.7 ± 0.6 µM) [Figure 6].
50
50
A promising class of covalent inhibitors of HNE with high selectivity is a group of sulfur fluoride exchange
(SuFEx)able derivatives. From a set of 105 synthesized compounds, a simple benzenoid compound 24 (8),
2-(fluorosulfonyl)phenyl fluorosulfate, shows the best potential to inhibit HNE [Figure 6]. In a kinetic assay
using MeOSuc-AAPV-AMC as a substrate, after 10 min of incubation, compound 24 obtains the best
results with an IC value of 0.24 ± 0.02 μM. 2-(fluorosulfonyl)phenyl fluorosulfate in a test against a panel of
50
serine proteases proves selective inhibition of HNE without the inhibitory effect on CatG .
[40]

Compounds belonging to benzenesulfonic acid derivatives are known as competitive inhibitors of HNE.
According to Xu et al., from a series of synthesized ortho- and meta-substituted benzenesulfonic acids, only
one, a compound 4f (9), shows moderate activity toward HNE, with an IC value of 35.2 µM [Figure 7].
[41]
50
The cytotoxicity of the chosen compound was measured with five mammalian cancer cell lines, including
MCF-7, BGC823, A549, HepG2, and HTC116, and no inherent cytotoxicity was observed .
[41]
Sulfonated nonsaccharide heparin mimetics are a group of novel potent, selective, non-competitive, and
allosteric HNE inhibitors, without specificity toward other proteases, like plasmin, trypsin, and
chymotrypsin, as well as heparin-binding coagulation proteins. Compound 3 (10), a hexa-sulfonated
derivative, shows the most potent HNE inhibitor activity with an IC value of 0.22 ± 0.00 µM [Figure 8].
50
However, this compound does not scientifically affect the proliferation of the three human cell lines,
including MCF-7, CaCo-2, and HEK-293 at a concentration of up to 10 µM .
[42]