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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_6035_Библиотеки_им_академика_М_И_Перельмана.pdf
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markets in China. NPs derived from Traditional Chinese Medicines (TCMs) represent a
valuable source of structurally diverse bioactive compounds for potential drug discovery.
FIGURE 14.27 Chemical structures of dipeptide asperphenamate (91) isolated from raw malt.
⏎
At an initial concentration of 12.5 µg/mL, the researchers screened several TCM extracts
to identify potential antiviral agents against loviruses and emerging viral pathogens. This
screening unveiled that extracts from the Rhodiola rosea plant exhibited specic inhibitory
effects on the entry and infection of both EBOV and MARV. Additionally, two chemically
related compounds, gallic acid (92) and ellagic acid (93), were isolated from R. rosea
(Figure 14.28). These compounds demonstrated the ability to effectively hinder EBOV
entry and, to a somewhat lesser extent, MARV entry.
FIGURE 14.28 Chemical structures of gallic acid (92) and ellagic acid (93) isolated from R. rosea.
⏎
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These ndings underscore the potential of R. rosea, and potentially other TCMs, as
potent anti-EBOV agents that warrant further exploration and development as antiviral
therapies. The screening approach primarily focused on targeting the viral entry process,
which is regulated by the glycoproteins (GPs) found on the viral particle’s surface.
The unaltered structure of EBOV and MARV GP consists of a trimeric arrangement of
GP1/GP2 heterodimers. GP1 is responsible for recognizing and binding to receptors, while
GP2 facilitates fusion between the viral and host cell membranes within the endosome. Both
EBOV and MAR V GPs can recognize attachment factors like glycosaminoglycans and C-type
lectins, thereby facilitating the internalization of viral particles through macropinocytosis.
Once inside the host cell, the virions traverse the endosomal–lysosomal system. The
GPs undergo cleavage by Caths B and L (Schornberg et al., 2006), exposing a specic
region of the GP that allows it to bind to Niemann-Pick C1 (NPC1), the internal receptor
for EBOV and MARV. This cathepsin-mediated cleavage of the GP triggers a critical
conformational change required for subsequent fusion (Brecher et al., 2012).
Caths B and L are essential for activating EBOV but not MARV GPs to facilitate
efcient entry into cell lines and macrophages, independent of TMPRSS2 expression
(Gnirss et al., 2012). Interaction between the GP and NPC1 is crucial for the fusion of
the viral membrane with the host endosomal membrane. This fusion transpires within late
endosome/lysosome compartments, liberating the viral capsid into the cell cytoplasm and
initiating viral genome replication.
The results from time-of-addition experiments suggest that the inhibitors primarily act
at a postbinding step in the endosome. Here, the Cath B inhibitor or entry inhibitor binds
to the EBOV–GP protein, disrupting GP-mediated fusion within the endosome. Ellagic
acid (93) exhibited an IC50 value of 1.4 µM against EBOV and 6.4 µM against MARV
pseudovirions, surpassing the antilovirus activity of gallic acid (92), which displayed
IC50 values of 10.5 and 25.4 µM, respectively.
Furthermore, both compounds exhibited negligible toxicity in A549 cells, with CC50
IC50 values of 309 and 122 µM for gallic acid ( 92) and ellagic acid (93), respectively.
These results suggest that gallic acid (92) and ellagic acid (93) are likely the major active
components contributing to the antiloviral activity of R. rosea.
In testing, the extract from R. rosea, along with gallic acid (92) and ellagic acid (93),
effectively inhibited infectious EBOV in HeLa cells. The IC50 value for the R. r osea extract
was determined to be 3.9 µg/mL, whereas gallic acid (92) and ellagic acid (93) exhibited
IC50 values of 25.4 and 10.5 µM, respectively.
These ndings emphasize the potential of exploring TCMs and NPs as promising candidates for the development of antiviral treatments against EBOV and other viral pathogens
(Cui et al., 2018).
Phenolic compounds, such as caffeic acid (94) and its derivatives, have been studied for
their inhibitory activity against human Caths B and L (Figure 14.29). The most promising
nding of this investigation is that caffeic acid (94) inhibited Cath B, with an IC50 value
of 110 µM. Caffeic acid acts as a linear inhibitor through mixed mechanisms, binding to
both the enzyme and the enzyme-substrate complex with different afnities. Caffeic acid
(94) not only selectively inhibits Cath B but also preferentially inhibits its endoproteolytic
activity without affecting the peptidyl-dipeptidase activity (Ulčakar and Novinec, 2021).
345
FIGURE 14.29 Chemical structures of caffeic acid (94).
⏎
Zingiber ocinale Roscoe, commonly known as ginger, belongs to the family
Zingiberaceae. Ginger rhizomes originate from southeastern Asia and have been used
in traditional medicine for centuries to treat various rheumatic diseases, including osteoarthritis (Srivastava and Mustafa, 1992). Cath K has recently emerged as an important
therapeutic target for osteoarthritis, driving the discovery of drugs aimed at preventing
bone and cartilage destruction. Studies have demonstrated the potential benets of
ginger extract in the treatment of osteoarthritis (Funk et al., 2009). In a clinical trial,
osteoarthritis patients received ginger extract and experienced a reduction in symptoms
with a high level of safety (Altman and Marcussen, 2001). 6-Shogaol (95) is the most
active derivative of ginger and has been isolated from ginger (Villalvilla et al., 2014)
(Figure 14.30). 6-Shogaol (95) inhibits TLR4-mediated inammatory responses and Cath
K activity through a completely uncompetitive mechanism (with an αKi value of 16.65
µM). Specically, 6-shogaol (95) blocks TLR4-mediated nitric oxide (NO) production
and reduces IL-6- and MCP-1-induced expression. Increased NO levels are known to
induce chondrocyte apoptosis, matrix degradation, and promotion of chondrocyte inammatory responses. Inhibition of NO production by 6-shogaol (95) may contribute to the
improvement of cartilage inammatory and degradative processes. Furthermore, the
reduction of IL-6- and MCP-1-induced expression by 6-shogaol (95) may also improve
these processes, as both factors play a key role in the progression of osteoarthritis. During
the osteoarthritis process, these innate immune responses are accompanied by increased
degradative activity supported by elevated MMP expression (Villalvilla et al., 2014).
FIGURE 14.30 Chemical structures of 6-shogaol (95) isolated from Zingiber officinale Roscoe.
⏎
Likewise, Silva et al. (2021) conducted a bioassay-guided study using ginger. They
isolated and identied 15 compounds from the dichloromethane soluble fraction of ginger.
The inhibitory activity against Caths K, L, and V enzymes was determined. The compounds
346
showed moderate inhibitory activity against only Cath K at an initial inhibitor concentration of 125 μM, with the highest inhibitory effects observed for compounds (96)–(100)
(Figure 14.31). Compound (98) exhibited the greatest inhibitory effect on Cath K, followed
by compounds (96)–(98), and (100). The IC50 values for compounds (96)–(100) were
determined to be 10.4, 21.1, 5.8, 54.4, and 55.3 µM, respectively . All compounds displayed
greater selectivity for Cath K. Compound (98) showed higher selectivity for Cath K over
Cath V, while compounds (96) and (97) showed higher selectivity for Cath K over Cath L.
The observation revealed that compounds with a larger side chain demonstrated increased
inhibitory activity against Cath K, indicating that hydrophobicity plays a crucial role as
a physicochemical factor for bioactivity within this compound class. For [10]-gingerol
(96), the inhibition type was determined to be uncompetitive (with a Ki value of 10.8 μM).
[10]-Gingerol (96) was docked onto the allosteric site of Cath K, corroborating the experi-
mentally determined inhibitory effect. Recently, the signicant potential of [10]-gingerol
(96) in inhibiting osteoclastogenesis has been discovered (Zang et al., 2021), reinforcing
its potential as a candidate for an antiresorptive drug.
FIGURE 14.31 Chemical structures of [10]-gingerol (96) and derivated (97)–(100) isolated from Zingiber
officinale Roscoe.
⏎
347
Cath L is a CP found within endosomes, and it plays a pivotal role in cleaving the S1
subunit of the coronavirus surface spike GP. This cleavage event is essential for facilitating
coronavirus entry into human host cells, promoting fusion between the virus and the host
cell endosome membrane, and releasing viral RNA for subsequent rounds of replication.
When SARS-CoV -2 enters intracellular endosomes, Cath L emer ges as the primary protease
responsible for cleaving the virus’s S1 subunit. Notably, this CP functions most effectively
under acidic pH conditions (Gomes et al., 2020). The development of Cath L-selective
inhibitors holds great potential for blocking coronavirus entry into host cells and providing
a mechanism to prevent SARS-CoV-2 infection in humans. Cath L has been demonstrated
to be important for virus entry and possibly exit during the late stages of infection. Drugs
that can inhibit Cath L offer potential therapy for COVID-19.
Utami et al. (2022) conducted a comprehensive computational docking analysis,
specically focusing on Cath L, to evaluate the inhibitory activity of bioactive compounds
isolated from Stachytarpheta jamaicensis for their potential role in COVID-19 drug therapy .
S. jamaicensis is a plant from the Verbenaceae family that is commonly used for medicinal
purposes. T en NPs were described in the extracts of S. jamaicensis: α-spinasterol, apigenin,
luteolol-7-glucuronide, friedelin, hispidulin, chlorogenic acid, ipolamiide, geraniol,
hentriacontane, and γ-aminobutyric acid. All compounds were selected as ligands. Among
them, α-spinasterol, apigenin, luteolol-7-glucuronide, friedelin, hispidulin, chlorogenic
acid, and ipolamiide showed a stronger afnity for the active site of Cath L. Apigenin
demonstrated the best afnity with signicant hydrogen bonding (Utami et al., 2022). The
current research indicates that S. jamaicensis compounds can be used as inhibitors for Cath
L and as potential drug candidates for COVID-19.
14.4 CONCLUSION AND FUTURE PESPECTIVES
The exploration of NPs for drug discovery holds immense potential, offering a vast array of
diverse structures and bioactivities that can serve as valuable starting points for novel drug
development. To fully harness the potential of NPs, it is essential to adopt a multidisciplinary approach and foster collaboration among experts from various scientific areas. By
combining knowledge in chemistry, pharmacology, molecular biology, and genetics, we
can maximize the chances of success in discovering and optimizing NP-based inhibitors
and lead compounds. Utilizing a wide range of scientific tools and techniques is crucial to
enhance the efficiency and effectiveness of the discovery process.
It is noteworthy that a signicant proportion of clinically approved protease inhibitors
can be traced back to NPs or nature-inspired compounds. This highlights the valuable role
that NPs have played in the development of critical class drugs such as protease inhibitors.
Even in ongoing clinical trials, NP-related and inspired compounds continue to contribute
to the development of small molecule protease inhibitors.
As the demand for new drugs and therapeutic agents continues to grow , it is imperative
that we take specic actions to protect and develop our environment under sustainable
conditions. By doing so, we can ensure that the window of opportunity for the discovery of
new medicinal and biological agents remains open. The continued exploration of NPs and
348
the application of advanced scientic approaches hold tremendous promise for the future
of drug discovery and the improvement of human health and longevity.
In summary, the search for NPs as inhibitors of cathepsins holds great signicance in
the eld of drug discovery. NPs offer unique chemical structures and diverse bioactivities
that can be utilized or optimized to develop novel drugs targeting cathepsins. They not only
expand the repertoire of therapeutic options but also provide opportunities for discovering
new mechanisms of action. With continued scientic and technological advancements,
NP-based drug discovery will continue to make substantial contributions to human health
and longevity.
KEYWORDS
• natural products
• cathepsins
• proteolytic activity
• Ebola virus
• mitogen-activated protein
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