new drug discovey
TRANSCRIPT
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New Drug
Discovery
by
Md. Monirul Islam
Pharmacy Discipline
Khulna University
Bangladesh
1. Introduction
Humans have long sought medicines, antidotes, palliatives and other bioactive materials
that positively affect health from their environment. From early medicinal treatments such
as willow bark tea for pain to the far more efficacious current-day pharmaceuticals which
include cholesterol lowering statins, anti-cancer drugs, narcotic analgesics such as the
opioids and non-narcotic analgesics such as ziconitide, or antibiotics are directly derived
from natural product research. Research and successful development of pharmaceutical
agents continues to remind us that the natural world remains an incompletely mined source
of novel pharmaceutical agents. The marine environment has been less effectively mined to
date than terrestrial environments due to its inherent inaccessibility and the difficulty of
preserving and transporting samples from their origin to the laboratory. The marine
environment represents a unique evolutionary niche yielding unique bioactive molecules.
2. New drug discovery from marine sources
Discovery of novel natural products is an accepted method for the elucidation of
pharmacologically active molecules and drug leads. Natural products from filter feeding
marine invertebrates and in particular, sponges, have proven to be a rich source of
structurally unique pharmacologically active compounds, with over 16,000 molecules
isolated thus far and a continuing pace of discovery at hundreds of novel bioactive
molecules per year. All classes of pharmaceuticals have been represented in this discovery
process, including antiprotazoals, TGF-beta inhibitors, cationic channel blockers, anticancer,
cytotoxic, antiviral, anti-inflammatory and antibacterial compounds.
3. Sources of marine natural products
There have been reviews on aspects of the chemistry and bioactivity of compounds from
microbes, soft corals, cyanobacteria and microalgae, sponges, echinoderms, ascidians, fish,
the sponge genus Halichondria, terpenes from the soft coral genus Sinularia, coelenterates,
tunicates, opisthobranch mollusks, echinoderms.
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4. Marine natural products being the new source of lead compounds
Marine organisms have evolved to produce distinct and dynamic molecular responses due
to the stressors in their environment, such as nearly ubiquitous bacterial and viral
competition and attack, and continuously variable environmental parameters such as
salinity or pH. Additionally, marine organisms tend to share a higher degree of networked
interconnectedness than land organisms, and do not suffer from degenerative diseases
similar to mammalian life. As example, aging mechanisms differ or are absent (i.e., no
telomere shortening is observed), and cancer and cardiovascular disease (or more
accurately, its equivalent) are unobserved. Thus, the marine ecosphere may be considered a
unique evolutionary niche which has given rise to a dynamic, diverse type of novel
molecular structures.
5. Marine natural products as drugs
5.1. Eribulin mesylate
Eribulin isolated from Halichondria okadai was
approved by FDA in 2010 to treat patients with
metastatic breast cancer who have received at
least two prior chemotherapy regimens for late-
stage disease.
Fig: Structure of eribulin.
5.2. Discodermolide
Discodermolide, a polyhydroxylated lactone
structure, was isolated from the marine sponge
Discodermia dissoluta and originally found to have
immunosuppressive activity. (+)-Discodermolide is
now in Phase I clinical trials as a potential drug for
solid tumors. Fig: Structure of discodermolide.
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5.3. Dolastatin-10
Dolastatin-10 and its related congener
Dolastatin-15 are polypeptide natural
products which were isolated from
marine sea hare Dolabella auricularia.
Both of these compounds are more
potent than vinblastine in tubulin
polymerization assays. Fig: Structure of dolastatin-15.
5.4. Didemnin B
Didemnins are cyclic depsipeptide compounds
isolated from a tunicate of the genus Trididemnum
that were collected in the Caribbean Sea. Didemnin B
is the one that possesses the most potent biological
activities. This compound, though, is too toxic to be
useful as antiviral or immunosuppressive agent; it has
been in Phase I clinical trials as an anticancer agent.
Phase II clinical trials are underway.
Fig: Structure of didemnins.
5.5. Bryostatin 1
The Bryostatins are macrocyclic lactones isolated from
the marine bryozoan Bugula neritina and found to
possess both antineoplastic and immunopotentiating
properties. Bryostatin 1 was originally described on
the basis of inhibiting growth in murine P388
lymphocytic leukemia cells at subnanomolar
concentrations. A range of properties have
subsequently been described including activation of T-
cells, immunomodulation and stimulation of
haematopoietic progenitor cells. Fig: Structure of bryostatin.
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5.6. Manzamine A
Manzamine A, a beta-carboline alkaloid present in
several marine sponge species, has potent
inflammatory activity, antifungal, anti-HIV-I
activities with moderate antitumor activity. These
compounds were isolated from E. rufescens. The
anti-malarial effect of manzamine A was due to
inhibition of the growth of the rodent malaria
parasite Plasmodium berghei in vivo.
Fig: Structure of manzamine.
6. Future aspects of marine natural products
The marine environment, a virtually untapped resource to date, holds great promise as a
rich source of novel bioactive molecules, for discovery of both novel pharmaceutical agents
and nutraceuticals, which have significant overlap with pharmaceuticals (as example,
carotenoids can function as antioxidants, or as various potent cytotoxic agents). Mining
genomes to discover such novel, bioactive natural products is a powerful and effective
discovery modality that is actively being developed by laboratories around the world. The
goal is to conduct, as available, whole genome, proteome, transcriptome, lipidome or
metabolome analyses to discover novel marine bioactive, pharmaceutical, and nutraceutical
agents, with the overall vision and goal of improving human health.
7. Conclusion
Natural products have played a significant role in drug discovery. Over the past 75 years,
natural product derived compounds have led to the discovery of many drugs to treat human
disease. Drugs developed from marine sources give us this hope and also give us novel
mechanisms to fight some of the most debilitating diseases encountered today, including:
HIV, osteoporosis, Alzheimer’s disease and cancer.
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8. References
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Publishers. ISBN 1-4020-3472-5 and ISBN 1-4020-3484-9 (e-book). 2005.
2. Joseph, B.; Sujatha, S. Pharmacologically Important Natural Products from Marine
Sponges. J. Nat. Prod. 2011, 4, 05-12.
3. Orhan, I.; Şener, B.; Kaiser, M.; Brun, R.; Tasdemir, D. Inhibitory Activity of Marine
Sponge-Derived Natural Products against Parasitic Protozoa. Marine Drugs 2010, 8, 47-58.
4. Fenical, W. Natural Products in the Marine Environment. Science 1982, 215, 4535, 923-
928.
5. Cragg, G.; Newman, D.; Snader K. Natural Products in Drug Discovery and Development. J.
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7. NP.Searcher http://dna.sherman.lsi.umich.edu.
8. Wikipedia free encyclopedia website: http://en.wikipedia.org
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