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13.11.2 PLITIDEPSIN
It is a didemnin, which is a type of chemical found in Trididemnum solidum.
The eukaryotic elongation factor 1 alpha 2 (eEF1A2) protein is essential for plitidepsin’s
function. Apoptosis is the end outcome of a cascade of events that begins with this interaction
promoting early oxidative stress, which in turn rapidly activates c-Jun N-terminal kinase
(JNK) and p38/MAPK. Plitidepsin’s possible usefulness in the therapy for treating multiple
myeloma (MM) follows its investigation for a wide range of malignancies. Overexpression of
eEF1A2 in diseased B cells is responsible for this action. The patient was previously treated
with dexamethasone and at least three different regimens before receiving this treatment
as part of the phase III clinical research known as ADMYRE (NCT01102426). Although
the medication’s benets have been downplayed due to concerns about its negative effects
(Vuong, 2021). Despite this, the benets of the medication have been judged to be limited;
hence, the usage of this chemical has not been extended to other nations. Clinical trials and
early data have been undertaken to see if plitidepsin could be used to treat COVID-19 in
certain people, but this approach still needs additional study. However, in recent case report
research for chronic lymphocytic leukemia (CLL), SARS-CoV-2 nucleocapsid (N) protein
synthesis was blocked by plitidepsin because of the protein’s ability to inhibit elongation
factor 1 (eEF1A) (Barreca et al., 2020).
13.11.3 TRABECTEDIN
Trabectedin was originally isolated from the Caribbean tunicate Ecteinascidiaturbinata as
part of the National Cancer Institute’s, Bethesda, screening ef fort of marine natural products
in the 1960s. Because of its unique molecular structure, this alkaloid molecule hardly occurs
naturally in marine organisms. Two rings of tetrahydroisoquinoline (THIQ) are bonded
together by a lactone bridge to form its structure. It took a lot of work and 20 years of
research after the structure was discovered to characterize it and figure out how it worked.
The interaction of Trabectedin with DNA is responsible for the cytotoxic effect against
cancer cells. The massive molecule alkylates DNA in the minor groove, where it disrupts the
function of DNA repair-related proteins, transcription factors, and other components. This
causes cells to undergo apoptosis and disruption of cell cycle. The effects of Trabectedin
on cancer cell lines were studied in vitro, with researchers looking specifically at the drug’s
ability to halt RNA polymerase II’s elongation process. During transcription, RNA Pol II
comes into contact with Trabectedin, which inhibits its ability to go further down the strand.
This obstruction causes ubiquitination of the RNA transcript, which in turn activates the
proteasome to destroy the RNA transcript (Giddings and Newman, 2022).
13.11.4 LURBINECTEDIN
Lurbinectedin is alkaloid isolated from Ecteinascidia turbinata. The C ring of this
compound is different from that of THIQ in that it contains a tetrahydrocarboline instead
of a tetrahydroquinoline. Patients with small-cell lung cancer who have progressed despite
platinum-based chemotherapy will be able to use this medication beginning in 2020 thanks
304
to the FDA approval. Metastatic small-cell lung cancer is treated effectively. The medicine
works in a manner analogous to that of Trabectedin by binding to DNA in the minor groove
in GC-rich areas, hence interfering with transcription and the repair process. Nonetheless,
adducts persist in being created, setting off a chain reaction that impairs DNA-binding protein
activity , transcription factor function, and repair pathway function, leading to double-strand
breaks and cell death. Furthermore, Lurbinectedin can inhibit the interaction of transcription
factors with DNA. It is known that the oncogenic transcription factor EWS-FL1 is present in
pediatric Edwing sarcoma, and that it is also responsible for the development of other types
of cancers. While the actions of Lurbinectedin and T rabectedin on cells are quite similar due
to the fact that they are both the derivatives of the same molecule, the anticancer activity
that they exert may be accomplished in two different ways. This may be thought of as a
more targeted form of the first mechanism. Lurbinectedin, much like Trabectedin, has the
ability to reduce the number of macrophages that are linked with tumors by modifying the
microenvironment of the tumor (Barreca et al., 2020).
13.12 MARINE NATURAL PRODUCTS AS ANTICANCER DRUGS
It took anywhere from 20 to 30 years for four marine treatments to become available on the
market via the process of lead disclosure; nevertheless, FDA has already given its approval.
The following table provides an overview of some anticancer drugs that have their roots
in marine life. In the disciplines of hematology and oncology, several medicines derived
from marine sources that have significant anticancer effects are now going through various
stages of clinical development (Al-Rajhi et al., 2022).
Only four marine-derived drugs have been approved for use in medicine since cytarabine’s introduction more than half a century ago, and even fewer marine-derived anticancer
drugs are in Phase I, II, or III clinical trials at present (T able 13.2). Clinical tests are broken
up into four distinct steps: the rst three take place before the medicine is introduced to
the market, while the fourth step begins after the drug has already been used and continues
until the end of product’s lifecycle. While the study was in the preclinical stage, did any
potentially dangerous trends emerge? How potent is the medication when it is taken in
accordance with the prescribed protocol? Are there any signicant problems that still need
to be solved in the formulation or manufacturing stages? How does the copyright system
work? How would you characterize the current state of the market? What will in the future
be renowned for its competition in the present? And maybe most crucially, what is the
likely price that will be asked for the item? After then, the investigational medicine is
subjected to the second phase of clinical tests, which serves the purpose of assuring that
specic issues may be adequately answered.
13.13 LIMITATIONS OF MARINE NATURAL PRODUCTS AS SOURCE FOR
ANTICANCER AGENTS
A bottleneck that frequently appears during the process of creating pharmaceuticals from
marine life is the constant availability of large numbers of organisms with chemicals that do
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TABLE 13.2 Anticancer Compounds Isolated from Marine Sources (Shahid et al., 2022)
⏎
Compound/Class Marine Source Activity Against Mechanism
Apratoxin A/Peptide
Brugine/Alkaloid
Fucoidan/Polysaccharides
Lyngbyabellin B/Peptide
Sansalvamide A/Peptide Marine fungi Cancers of the
Scutellarein 4′-methylether/
Polyphenol
Phlorofucofuroecol A/
Polyphenol
Phloroglucinol/polyphenol Brown seaweed Colon cancer At 300 µM concentration, DNA
Heparin/Heparan/
Polysaccharides
Chondroitin-4-sulphate/
Polysaccharides
Chondroitin-6-sulphate/
Polysaccharides
Lyngbyaboulloni
(cyanobacteria)
Bruguierasexangula
(plant)
Ascophyllum nodosum
(algae)
Lyngbya majuscule,
(cyanobacteria)
Osmundea pinnatifida
(algae)
Brown seaweed Cancer Not mentioned
Dictyopterisdelicatula
(Seaweed)
Cucumariafrondosa
(sea cucumber)
Cucumariafrondosa
(sea cucumber)
Cervical cancer IC50 = 2.2 nM for cell cycle
inhibition
Sarcoma 180 and
Lewis
Colon cancer At concentrations between 80
Malignant Burkitt
lymphoma
pancreas, colon,
breast, and prostate
Choriocarcinoma Not mentioned
Colon cancer Between 80 and 100 μg/mL
Cancer Not mentioned
Cancer Not mentioned
Not mentioned
and 100 µg/mL, the growth of
arterial smooth muscle cells is
inhibited.
IC
= 0.02 µM for inhibition of
50
cell growth
Inhibits protein complex
formation
damage is induced resulting in
cell death.
concentrations, arterial smooth
muscle cell growth is inhibited.
not harm the marine ecosystem. This is a vital stage in the process. Marine pharmaceuticals
will only have a chance on the market if there is a supply problem that can be solved in a
manner that is both economically and environmentally viable. Chemical synthesis/semisynthesis/modification, as well as marine biotechnology procedures, offers potential solutions
to the supply dilemma. Marine biotechnology offers a solution to the supply problem if
sustainable collection from the natural environment is not possible (Khalifa et al,. 2019).
13.13.1 AQUACULTURE/CULTIVATION
Aquaculture is a well-established method for the production of marine creatures for human
consumption, such as fishes or some mussels, as well as macroalgae. It is possible to cultivate
macro- and microalgae in bioreactors, together with some kinds of invertebrate cells, several
species of marine fungus, and a number of different forms of marine bacteria. Unfortunately ,
the bulk of pharmaceutically intriguing marine creatures, particularly bacteria, are unable
306
to be cultivated under artificial circumstances. This is especially true for marine organisms
that live in water. To create alternative techniques of cultivation and to keep the metabolite
production going for a long time, it is vital to have a better grasp of the living circumstances
that exist in the natural environment. This method has the potential to be very successful.
Cocultivation has been shown to increase the chemical diversity of metabolites produced
by the cultivated organisms. It causes a dramatic upsurge in the production of chemicals
already present in the organism and/or the accumulation of cryptic compounds invisible in
axenic cultures of the producing strain (Parthasarathy et al., 2020).
13.13.2 GENETIC ENGINEERING
This approach works by transferring the genetic information necessary to produce the
desired molecule into host cells, which are then able to produce the compound in a manner
that is both sustainable and easy to culture. The precise understanding of the genetic information is required as a prerequisite. These procedures would make it possible to isolate and
express the genes of creatures that cannot be grown in a laboratory setting. This method has
been implemented on a research scale, but it has not yet been used on an industrial scale for
marine pharmaceuticals that are for sale (Santos et al., 2020).
13.13.3 SYNTHESIS/SEMISYNTHESIS/MODIFICATION
The entire synthesis of many of the known marine chemicals is theoretically conceivable,
but it can only be economically implemented for items that are reasonably straightforward.
One example of this would be the analgesic peptide ziconotide. An additional method is
the semisynthetic production, which involves transforming readily accessible molecules
into the desired product via the use of chemical or biological transformation processes.
The creation of the antibiotic Trabectedin, which involves the transformation of the
bacterial byproduct cyanosafracin B, is a good illustration of this idea. In most cases, the
first chemical discovered naturally is a “lead structure,” meaning that it is not necessary
to generate the entire structure. We can better focus on the crucial structural components
once we have a better understanding of the structural requirements for pharmacological
action. Synthetic halichondrin derivative eribulin has a much smaller molecular size than
its natural analog, halichondrin. Chemical or enzymatic alterations to the natural substance
serving as the lead structure can increase structural diversity and improve product attributes
(Santaniello et al., 2023).
13.14 CONCLUSIONS AND FUTURE PROSPECTS
Maritime domain offers an extraordinary possibility for the pursuit of innovative anticancer
goods and is an enormous means of isolating various cell foci for therapeutic intervention.
Both these benefits are provided by the marine environment. The FDA has only given its
commercial approval to a small number of anticancer therapeutic pharmaceuticals, such as
®
Depocyt
, Y ondelis®, AdcetrisTM, and Halaven®, and simply a small number of anticancer
therapeutic treatments are now in the late stages of clinical trials for various conditions.
307
As a result, there is a significant gap between the distribution and use of anticancer
medications for clinical testing. Chitosan, a marine biopolymer, continues to hold much
potential as an outstanding resource for the development of marine therapeutic applications.
At the present time, anticancer medicines derived from marine sources are being employed
to precisely control endogenous immune processes against a variety of cancers that are
lethal. Inhibiting the JAK/STAT innate immune signaling system has also been crucial in
the development of key anticancer qualities in a number of drugs, including aparatoxin A.
This is a form of intercellular communication that is used by cancer cells. Despite their
importance, marine anticancer drugs have not undergone extensive clinical testing of the
signals regulated by cGAS-STING. This is despite the fact that these signals are quite
important. There are substantial barriers in the way of developing anticancer medications
that are derived from marine organisms at the moment. The development of marine
pharmaceuticals would be greatly aided by a comprehensive interdisciplinary partnership
among scientists, chemists, biotechnologists, pharmacists, and medical practitioners, as
well as between universities, clinics, and businesses. This would allow for the challenges
and limitations to be overcome. Fast realistic methods are required to quickly grasp
innovative findings into complicated therapies for life-threatening cancer conditions and to
enhance the general state of human health. In addition, the utilization of marine medicines
and their associated generic molecules may shed light on the development of novel clinical
anticancer therapies, either alone or in conjunction with other chemotherapeutic drugs.
Whether the marine drugs or their generic analogs are taken alone or in conjunction with
other chemotherapeutic treatments, this remains true. Advanced technologies including
analytical spectrometry , computational genetics, gene mining, and experimental treatments
will need to be used in the near future to effectively explore novel structures in marine
natural product development.
KEYWORDS
• marine natural products
• anticancer
• bioactive compounds
• marine organisms
• drug discovery
• chemical diversity
• mechanisms of action
• preclinical studies
• clinical studies
• biotechnology
• synthetic biology
308
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CHAPTER 14
Natural Products as Novel Opportunities for Cathepsin Inhibitors
EMERSON FINCO MARQUES
ABSTRACT
Natural products (NPs) have long been recognized and utilized for their therapeutic
properties, with a particular focus on their potential in drug discovery for cancer and
infectious diseases. Cathepsins, a class of proteolytic enzymes, have been extensively
studied due to their involvement in a wide array of physiological and pathological
processes. The dysregulation of cathepsins has been associated with sicknesses, including
inflammation-related conditions, cancer, arthritis, neurodegenerative disorders, and
cardiovascular diseases. Natural compounds derived from bacteria, fungi, marine organisms,
and plants with protease inhibitory activity, have garnered attention for their potential in
drug discovery. This chapter explores the diverse NP inhibitors targeting cathepsins and
their potential in drug discovery. The vast structural diversity of NPs serves as a valuable
resource for the development of new drugs, offering limitless opportunities for the
identification of novel molecules. Recent advancements in analytical tools, bioinformatics,
genome mining, and engineering strategies have addressed challenges in NP research and
opened new avenues for exploration. As a result, there is renewed interest in harnessing
NPs as leads for drug development. In this perspective, we provide an overview of NPs
exhibiting inhibitory effects on cathepsins with an aim to inspire research and exploration
related to drug discovery.
*
*Corresponding author
14.1 INTRODUCTION
Since the dawn of humanity, people have utilized natural products (NPs) from various
sources in nature for therapeutic purposes. Cuneiform records dating back to ancient
Mesopotamia (around 4000
medicinal and pharmacological prescriptions. The discovery of the first pharmacological
texts occurred in the ancient city of Ebla, currently located in Tell Mardikh, Syria. However,
a significant collection of approximately 5000 medical preparations was predominantly
bc) were inscribed on clay tablets, documenting numerous
312
obtained from the library of King Assurbanipal in Nineveh, an ancient Assyrian city in
Upper Mesopotamia, which is present-day Mosul in northern Iraq. Additionally , cuneiform
medical sources have been found in temples, hoards, and private libraries of other NeoAssyrian cities in Babylonia, spanning from approximately 600 to 300 bc (Böck, 2015).
Notably , oils derived from Cupr essus sempervir ens and Commiphora species mentioned in
cuneiform texts are still employed today for the treatment of coughs, colds, and inflammation (Cragg and Newman, 2005).
The rst evidence of modern medical care has been found in Ancient Egypt
(3300–525 bc). Egyptian society possessed advanced knowledge of anatomy, and many
diseases were described in detail. Medical papyri documented the diseases, diagnostic
methods, and various remedies used for treatment. The medicinal pharmacopeias included
a wide range of plant sources, minerals, metals, and even some animals. Ancient Egyptians utilized various parts of plants such as the whole plant, fruit, leaves, juice, or root.
Importantly , these plants were derived from different species. Some of these plants are still
used today. For instance, the fruit of Ammi majus, native to Egypt, was employed to cure
vitiligo. More recently , a compound called coumarin 8-methoxypsoralen has been isolated
from the plant and is now being used to treat vitiligo and psoriasis (Metwaly et al., 2021).
Historically, NPs have been incredibly successful in our society, originating from
microbial, plant, and even animal systems. NPs have played a pivotal role in drug
discovery and remain a major source of therapeutic agents and innovation for treating
various diseases, particularly cancer and infectious diseases (Clardy and Walsh, 2004). The
term “NPs” refers to any naturally occurring substance, generally referring to secondary
metabolites. It has been estimated that over 5% of newly discovered active substances
are NPs, and 46% are derived from secondary metabolites with synthetic modications
(Newman and Cragg, 2007). For example, in the eld of cancer, over several decades,
53.3% (40 out of 75) of small molecules are derived from NPs (Newman and Cragg, 2020).
Proteolytic enzymes, also known as proteases, catalyze the breakdown of proteins
through highly specic hydrolysis of peptide bonds. This unique characteristic has allowed
proteases to adapt to a wide range of conditions and employ different catalytic mechanisms
for substrate hydrolysis. Mammalian enzymes encompass ve catalytic types of proteases:
aspartic, cysteine, metallo, serine, and threonine (Turk, 2006). The precise cleavage of
proteins by proteases serves as a subtle means of regulation (Davie and Neurath, 1955; Davie
and Ratnoff, 1964). These enzymes play a crucial role in normal biological processes, such
as cell death, proliferation, migration, invasion, and protein turnover (MacFarland, 1964).
Considering the functional importance of proteases in all living processes, the
rigorous control of proteolytic activity is essential for the normal functioning of an
organism to avoid potentially harmful excessive protein degradation. Impairments in
proteolytic functions are observed in cases of increased expression, reduced inhibition by
endogenous inhibitors, or misdirected temporal and spatial activity and underlie a wide
range of pathological conditions, particularly inammation-associated diseases, cancer,
arthritis, joint disorders, Alzheimer’s disease, multiple sclerosis, cardiovascular diseases,
bone disorders, obesity , and muscular dystrophy (Turk et al., 2000; Biasizzo et al., 2022).
Furthermore, modern genome mapping and sequencing of genetic mutations have revealed
that abnormal activity of individual cysteine cathepsins (Cath) can contribute to the