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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5400_Библиотеки_им_академика_М_И_Перельмана
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Strategy APP Formulation Target
bacteria or
disease
Keyindings Reference
Use of
prodrug
peptides
Prodrug
D-Bac8c
Liquid P.aeruginosa Three prodrugs
were cleaved by
puriied
neutrophil
elastase to be
activated and
exert
bactericidal
activity against
P.aeruginosa
with lower
cytotoxicity
[63, 64]
Prodrug
D-HB43
Prodrug
D-P18
Prodrug
D-WMR
Liquid Cystic ibrosis Prodrug D-WMR
inhalation
solution showed
promising
aerosol
performance
and retained its
antimicrobial
activity after
nebulization
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Strategy APP Formulation Target
bacteria or
disease
Keyindings Reference
Peptide
sequence
optimization
Alpha4-short Liquid P.aeruginosa The potency of
alpha4-short
against P.
aeruginosa
increased with
inlammatory
cytokines
markedly
reduced in a
murine lung
infection study
compared to the
original alpha4
peptide
[65, 66]
Pyocin S2,
Pyocin SD2
Liquid P.aeruginosa Intranasal
delivery of
pyocin SD2
reduced the
mortality of P.
aeruginosainfected mice
while the
original pyocin
S2 did not
decrease the
mortality
[22–24]
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Strategy APP Formulation Target
bacteria or
disease
Keyindings Reference
Use of host
antimicrobial
capacity
enhancer
APPs
IDR-HH2 Liquid Mycobacterium
tuberculosis
Intratracheal
instillation of
IDR-HH2 and
IDR-1018
peptide in
solution
suppressed the
growth of
Mycobacterium
tuberculosis and
decreased lung
inlammation in
a murine
tuberculosis
infection model,
while IDR-1002
treatment did
not reduce the
bacillary loads
during
treatment
[69]
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Strategy APP Formulation Target
bacteria or
disease
Keyindings Reference
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Strategy APP Formulation Target
bacteria or
disease
Keyindings Reference
IDR-1018
IDR-1002
LL-37 Liquid P.aeruginosa Intranasal
delivery of LL37 solution in a
murine lung
infection model
showed a
signiicant
clearance of P.
aeruginosa from
the lungs
[17]
SPA4 Liquid P.aeruginosa Intratracheal
treatment of
SPA4 solution
increased
phagocytic
uptake and
entry of P.
aeruginosa into
phagolysosomes,
leading to a
signiicant
reduction of
pulmonary
bacterial load
[18, 19]
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Strategy APP Formulation Target
bacteria or
disease
Keyindings Reference
ST3-H2A2 Liquid M.tuberculosi s Intratracheal
delivery of ST3H2A2 or
IL10R1–7
solution in M.
tuberculosisinfected mice
led to dosedependent
increased
antimicrobial
effect
[20]
IL10R1–7
Human
surfactant
protein
D(SP-D)
protein
Liquid Aspergillus
fumigatus
In a murine
aspergillosis
lung infection
model,
intranasal
delivery of SP-D
solution
decreased the
mortality rate
from 100% to
30% and
enhanced
protective
immunity to
Nippostrongylus.
Brasiliensis in
another study
[29, 70]
PA01
Flagellin
Liquid P.aeruginosa Intranasal
delivery of
puriied P.
aeruginosa
PA01 lagellin
improved lung
bacterial
clearance with a
90% reduction
in mortality in a
murine P.
aeruginosa lung
infection model
[32]
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Strategy APP Formulation Target
bacteria or
disease
Keyindings Reference
Recombinant
murine
Granulocyte/
Macrophage
Colony
Stimulating
Liquid S.pneumoniae Intratracheal
treatment with
adenoviral
recombinant
GM-CSF (AdGM-CSF) 3 days
prior to S.
pneumoniae
murine lung
infection
accelerated
bacterial
clearance by
approximately 2
log
10
[34]
New
nebulizers for
biologics
RR-11 Liquid Mycobacterium
smegmatis
Surface acoustic
wave (SAW)
nebulizer could
generate
inhalable
aerosols, and
maintain the
antimicrobial
activities of the
peptides
[76, 77]
RY-11
LK-8
MM-10
II-10
WW-10
Spray drying
and freeze
drying
Lysozyme Liquid/
powder
P.aeruginosa Different
nebulization
techniques had
different
impacts on the
stability of
lysozyme in
solution.
Inhalation
properties of
lysozyme
powders were
improved by
spray drying and
freeze-drying
[30, 79–
81]
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Strategy APP Formulation Target
bacteria or
disease
Keyindings Reference
Hydrogel Lysozyme Liquid P.aeruginosa Hydrogel
microspheres
were produced
to maintain
bioavailability
by protecting
lysozyme
against uptake
by phagocytic
cells in the lungs
[82]
Liposomal
formulation
Colistin and
CMS
Liquid/powder P.aeruginosa Colistin
liposomes
(positively
charged)
remained stable
over seven days
[78, 83]
Nanoparticles SET-M33 Nanoparticles P.aeruginosa The powder
formulations
had high
dispersibility
(ine particle
fraction of up to
68%) and
disintegrated
rapidly into
original
nanocomplex,
with a low
moisture
content (<5%)
and a high Tg
[84, 85]
Mesoporous
silica
particles
NZX Mesoporous
silica particles
M.tuberculosis NZX MSPs
possessed a drug
loading rate of
17% wt, and a
signiicantly
increased
bactericidal
activity (>20fold) than the
free NZX
[86]
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4.1 StrategiesinStabilizingandEnhancing
AntimicrobialPeptidesandProteinsforInhalation
Compared with small molecules, APPs require milder conditions to maintain
their molecular structures. Owing to the diversity of peptide and protein
structures, different strategies were employed for different APPs (Table 1).
4.1.1 EnantiomericOptimization
Enantiomeric optimization could potentially change the properties of the
original peptides, which may increase the chance of commercialization of the
inhaled drug. This is illustrated in the case of the WLBU2 peptide, which lost
its antimicrobial activity after 4 hours of incubation in the presence of
epithelial secretions, while its d-enantiomer D8 WLBU-2 remained stable
[56]. D8 WLBU2 also showed reduced toxicity and a higher therapeutic index
(i.e., the dose of drug that causes therapeutic effects relative to the dose that
causes adverse effects) [56].
4.1.2 D endrimerSynthesis
Dendrimer synthesis is another way of optimizing antimicrobial peptides to
be more stable in the presence of proteases [57]. For example, two-branched
dimeric form of the cationic antimicrobial peptide SET-M33 (SET-M33DIM)
has been produced [58], and it was resistant to a loss of activity in biological
luids and maintained its antimicrobial activity against drug-resistant isolates
in vitro and in vivo [57, 59]. According to other studies using various peptides,
it has been speculated that the enhanced stability of the peptide might be due
to its branched multimeric structure [60] and low amino acid frequency
between two branching points of the peptide [61]. Falciani et al. found the
occurrence of enhanced stability in enzyme proteolysis with the branched
multimeric peptides [60]. Sommer et al. showed that peptides with only one
amino acid between two branching points had signiicantly higher proteolytic
stability than those with two or three amino acids [61].
4.1.3 ProdrugPeptides
The use of prodrug peptides could potentially minimize lung proteaseinduced degradation, enhancing the safety and stability of the antimicrobial
peptides.
Forde et al. identiied a prodrug of a 13-residue peptide D-WMR that has
improved salt resistance with enhanced bactericidal activity in
bronchoalveolar lavage luid (BALF) from CF patients, as well as lower
immunogenicity and cytotoxicity [62]. In a subsequent study, pro-WMR, with
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an aerosol ine particle fraction (i.e., aerosols <5 μm) of 67% after
aerosolization using an Aerogen Solo vibrating mesh nebulizer, retained its
biological activity. Further, simulated breathing experiments conirmed that a
large proportion of the nominal peptide was expected to reach the deep lungs
[63]. In another study, three pro-peptides, D-Bac8c
2, 5 Leu
, D-HB43, and D-P18
8,
were cleaved by puriied neutrophil elastase to be activated and exert
bactericidal activity against P.aeruginosa with lower cytotoxicity. However,
the pro-peptides could only be activated by bronchial alveolar lavage in the
presence of sodium chloride [64]. These studies show the value of assessing
prodrug peptides for inhalational use to improve their therapeutic properties.
4.1.4 Peptide SequenceOptimization
Sequence modiication can affect the function of APPs. For example, alpha4short is a sequence-optimized (with a reduction in length and increase in the
number of positively charged amino acids) peptide from the synthetic shortpalate lung and nasal epithelial clone 1 (SPLUNC1)-derived alpha4 peptide
[65, 66]. The potency of alpha4-short against P.aeruginosa was increased
compared to the original alpha4 peptide [66]. Intratracheal delivery of alpha4short solution signiicantly decreased bacterial burden in BALF and lung
homogenate in a murine P.aeruginosa lung infection model. In addition,
inlammatory cytokines were markedly reduced compared to mice treated
with saline or alpha4, and the host toxicity of alpha4-short, including
hemolytic activity and leukopenia, was negligible at concentrations up to
64 μM [66].
Another example is pyocin. Pyocins are produced by P.aeruginosa strains,
which showed antibacterial activities for intraspecies competition [23]. In
one study, intranasal delivery of pyocin S2 solution did not reduce mortality of
infected mice 6 h after pulmonary inoculation of P.aeruginosa, with
approximately 10
5
CFU of P.aeruginosa remaining in the lungs. In contrast,
intranasal delivery of 75
μg of pyocin SD2 (N-terminal domains homologous
with pyocin S2 and C-terminal cytotoxic domain homologous with the tRNase
domain of colicin D) in solution resulted in survival of P.aeruginosa-infected
mice and reduction in bacterial load to only 5 CFU/lung. In addition, the
recovered colonies showed no resistance to pyocin SD2 [22, 24]. Sequence
optimization could potentially be applied to enhance the antimicrobial
activities of APPs.
4.1.5 UseofHostAntimicrobialCapacityEnhancerAPP s
Some antimicrobial capacity enhancer APPs target the pathogen indirectly by
stimulating the innate host defense system [67]. Most of these APPs are still at
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