Drug discoveryfrommarinesources

Drug Discovery from Marine Sources

Prof. Dr. Basvaraj K. Nanjwade M. Pharm., Ph. D

Department of Pharmaceutics
KLE University College of Pharmacy
BELGAUM-590010
Karnataka, INDIA

15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 1

INTRODUCTION

• Substances produced by living organisms
found in nature have played a critical role in
the development of drugs for life-threatening
conditions.

• Number of recent breakthroughs have resulted
in the development and approval of anticancer
drugs derived from marine sources such as
coral and sponges.

Drug Discovery Process and Productivity


Discovery Process and Productivity

• The discovery process begins with isolation of unique
microbes and generation of chemical extracts of biologically
active molecules produced by the microbes.

• Information on the microorganisms, their sources, culture and
extraction conditions, novel chemistries and biological
activities have been developed that allow for a concentrated
effort on the most productive organisms.

• Primary targets leads to identification of novel, biologically
active discovery leads in the selected therapeutic areas of
oncology and infectious diseases

Why Marine?

• The marine environment provides a broad
range of diverse habitats from which novel
sources of natural products can be derived.

• Studies from around the world have shown
that marine organisms produce a diverse
array of metabolites with novel chemical
structures and potent biological activities as
well as other desirable properties.

Marine Organisms


Marine Organisms for Drug Discovery

• Life has originated from the oceans that cover over 70% of the
earth’s surface and contain highly ecological, chemical and
biological diversity starting from microorganisms to
vertebrates.
• The source of unique chemical compounds, which hold
tremendous pharmaceutical potential.
• Sources emphasize on investigation of the marine ecosystem
to explore numerous complex and novel chemical entities.
• The sources of new leads for treatment of many diseases such
as cancer, AIDS, inflammatory conditions, and a large variety
of viral, bacterial and fungal diseases.



• Majority of the marine natural products have been
isolated from
• Sponges,
• Coelenterates (sea whips, sea fans and soft corals),
• Tunicates,
• Opisthobranch molluscs (nudibranchs, sea hares,
etc.),
• Echinoderms (starfish, sea cucumbers, etc.) and
• Bryozoans (moss animals) and a wide variety of
marine microorganisms in their tissues.


• Sponges, the most primitive multicellular
invertebrates, considered as a gold mine during the
past 50 years, have fascinated scientists for isolation
of promising bioactive compounds for human
welfare.

• Interestingly, cytarabine (Cytostar-U) also known as
Ara-C, a compound isolated from the Caribbean
sponge Cryptotheca crypta currently being used with
other anticancer drugs in the treatment of acute
myelocytic leukaemia (AML). Pune.
15th Nov. 2011 Poona College of Pharmacy, BVDU, 9

New Tools for Drug Discovery

• Exploration of new locations, collection of organisms
never before sampled, and identification of chemicals
with pharmaceutical potential.

• New and improved platforms (such as autonomous,
remote, and human occupied underwater vehicles) to
take us farther and deeper are in development.

• Tools and sensors that have been developed both for
space exploration and for diagnostic medicine

Harbor Bracnch Operates the Johnson-
Prospects for Success
Sea- Link class subs Depth capability: 3000 ft


An Excellent View


A Variety of Manipulator Tools


Unique Work Platforms


How do we choose dive sites?


600–800m

Resolution 20-50m


Sensors


Marine Biotechnology

• There are numerous opportunities to borrow scientific
techniques common to one discipline and apply them
innovatively to other areas and questions.

• Different marine cyanobacteria to help select the most
promising species for pharmaceutical drug discovery
efforts, and then using a genomics and molecular
biological approach to understand how their unique
natural products are created at a genetic and
biochemical level.

Marine Microbial Drug Leads

• The genomics revolution has recently provided an
orthogonal approach to the discovery of natural
product drug leads in which sequenced genomes are
“mined” for biosynthetic pathways.

• While promising, this emerging technology faces its
own challenges.


Genomic to Animal Marine

• Marine invertebrate animals provide a robust source
for the discovery of bioactive small molecules with
the potential to treat human diseases.

• Metagenomics affords an efficient and inexpensive
method to capture this chemical diversity.

• Metagenomics is providing renewed insights into
what chemical diversity means and how it originates
in the ocean.

Primary Metabolites

• A primary metabolite is a chemical substance
which is required for cells to survive and replicate
and is therefore required for survival of the
organism
• Examples are:
– Proteins
– Carbohydrates
– Lipids
– Nucleic acids


Secondary Metabolites

• A secondary metabolite is a chemical
compound produced by an organism which is
not required for survival of the organism but
presumably confers an evolutionary advantage


Drug Discovery and Development


Marine Drug Discovery and Development


Marine Biodiscovery Centre


Sources of Chemical Diversity


Generating Chemical Diversity


Uses of Chemical Diversity


Screening
• Purified extract library

• Pure compund library

• Structurally defined pure compound library


Expertise
• Structural characterisation of organic compounds and
element/isotope-tagged biomolecules
• Spectroscopic expertise:
– Nuclear magnetic resonance
– Liquid chromatography - mass spectrometry
– Inductively coupled plasma - mass spectrometry
(ICPMS)
– Elemental Imaging: laser ablation ICPMS
– Gas chromatography - ICPMS

Facilities
• 600 & 400 MHz Nuclear Magnetic Resonance
• High and low resolution LC-MS
• High and low resolution ICP-MS
• Parallel HPLC - ESMS/ICPMS
• Fully equipped microbial culture suite
• Separations/chromatography suite (eg SPE,
SEC, HPLC)


Process of Marine Drug Discovery

• Collection
• Biological Screening
• Natural Products Chemistry
• Secondary Testing/Pharmacology
• Production of material for clinical evaluation
• Clinical investigation


Marine Drug Discovery
• Requires a Multidisciplinary Team
• Biologists
- Marine Biologist
- Cell Biologists; Immunologists, Virologists
- Pharmacologists/Biochemists
- Molecular Biologists
• Chemists
- Natural Products Chemists
- Spectroscopists
- Synthetic/Medicinal Chemists
• Business Professionals
- Marketing/Technology Transfer/Patent Attorneys

Permits for Collections
• Before you collect-Get the right permits
• International Convention on Biological Diversity
– http://www.biodiv.org/convention/articles.asp
• You must have informed consent of host country
– Permits may be issued at a local or country level
– Work with State Governments for State waters; National marine Fisheries
for Federal
– Special Permits for Marine Sanctuaries
• Often a Memorandum of Understanding is negotiated prior to collection
– Participation by Host Nation in Project
– Return of Income/Benefit to Host Country
– Reporting requirements
– Sharing of specimens and information on samples

Collection Methods

1. Wading

2. Scuba

3. Trawling

4. Submersibles


Collection Strategies
• Biological Diversity = Chemical Diversity


Screening Approach


Finding Drug to Treat
• Cancer
- Pancreatic Cancer
- Multidrug resistant cancers
- Cancer “Specific” Agents (NCDDG)
• Infectious Disease
- Drug resistant staphylococcus aureus
- Anti-malarial-collaborative UCF, WRAIR
• Neurodegenerative Disease-collaborative
- Alzhemer’s
- Neuroprotection (Stroke)
• Inflammation-collaborative

ExtractsProspects for Success
are Complex Mixtures of
Marine Products


Natural Products Chemistry
• The Traditional Way


Purification


Anti-tumor agents from marine sources
currently licensed for development
Organism Metabolite Location Discoverer Current Status
Bryozoan: Bryostatin I Gulf of Pettit, In Phase
Bugula neritina California Arizona State I/IIclinical trials
Univ. in US/Europe;
NCI sponsored
trials.
Sea hare: Dolastatin 10 Indian Ocean Pettit, In Phase
Dolabella Arizona State I/IIclinical trials
auricularia Univ. in US; NCI
sponsored trials.

Tunicate: Ecteinascidin Caribbean Rinehart, Univ. Licensed to
Ecteinascidia 743 Illinois PharmaMar S.A.
turbinata In Phase II
clinical trials in
Europe and in
US.

Tunicate: Dehydro-didemnin Mediterranean Rinehart, Univ Licensed to
Aplidium B [Aplidine] Illinois PharmaMar S.A.
albicans
Gastropod: Kahalalide F Hawaii Scheuer, Univ. Licensed to
Elysia Hawaii PharmaMar S.A.
rubefescens
Sponge: Discodermolide Caribbean Gunasekera & Licensed to
Discodermia Longley, HBOI Novartis.
dissoluta

Sponge: Isohomo- New Zealand Munro & Blunt; Licensed to
Lissodendoryx halichondrin B Univ. PharmaMar S.A.
sp. Canterbury, NZ


Actinomycete: Thiocoraline Mozambique Canedo, Spain Licensed to
Micromonospora Strait PharmaMar S.A.
marina
Tunicate: Isogranulatimide Atlantic Andersen & Licensed to
Didemnum [Brazil] Bjerinck, Univ, Kinetik, Canada.
granulatum British Columbia
& Brazil

Sponge: Bengamide Fiji Crews et al. Synthetic
Jaspis sp Univ. California, derivative
Santa Cruz licensed to
Novartis.

Sponge: Hemiasterelins Papua New Andersen, Univ. Licensed to
Cymbastella sp. A&B Guinea British Columbia Wyeth-Ayerst.


Commercially available marine bioproducts

Product Application Original Source Method of
Production
Ara-A Antiviral drug Marine sponge, microbial
Cryptotethya cryta fermentation
of analog
Ara-C Anticancer drug Marine sponge, Chemical synthesis
Cryptotethya cryta of analog

Okadaic acid Molecular probe: Dinoflagellate Cell culture
phosphatase
inhibitor

Manoalide Molecular probe: Marine sponge, Wild harvest of
phospholipase A2 Luffariella variabilis sponge
inhibitor


Commercially available marine bioproducts

Product Application Original Source Method of
Production
Vent ® DNA Polymerase chain Deep sea Recombinant protein
polymerase reaction enzyme hydrothermal
vent bacterium
Formulaid ® Fatty acids used as Marine microalga Cell culture
(Martek Biosciences, additive
Columbia, MD) in infant formula
nutritional
supplement
Aequorin Bioluminescent Bioluminescent Recombinant protein
calcium indicator jellyfish,
Aequora victoria

Green Fluorescent Reporter gene Bioluminescent Recombinant protein
Protein (GFP) jellyfish,
Aequora victoria

THANK YOU
E-mail: bknanjwade@yahoo.co.in
Cell No: 0091 9742431000


Drug discoveryfrommarinesources

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