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Thai Professionals Conference 2010
CH3
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H 3C
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H
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CH3
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H3C
H
H
H
H3C
CH3
H
N
N
H
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DRUGS, NUTRACEUTICALS AND COSMECEUTICALS
FROM MARINE SOURCES - EU PERSPECTIVES
ANAKE KIJJOA
INSTITUTO DE CIÊNCIAS BIOMÉDICAS DE ABEL
SALAZAR
UNIVERSIDADE DO PORTO
PORTUGAL
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Special Acknowledgements
Ministry of Science, Technology and Environment
Office of Higher Education, NSTDA and TRF
The Thai Professional Award
In recognition of my outstanding contributions to Science and
Technology Development of Thailand
2-4 June 2008
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The oceans encompass about 71% of the surface of our
planet, and they represent the greatest extremes of
temperatures, light, and pressure encountered by life.
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Approximately 90% of the total global species live
in the marine habitat
Marine ecosystems are complex and dynamic. The
world’s ocean represent diverse environmental
niches, and have a large impact on our climate.
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Numbers of Marine NP for the period of 1965-2005
4500
Number of Compounds
4000
3500
3000
2500
2000
1500
1000
500
0
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Blunt et al. (2007) Nat Prod Rep
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Blunt et al. (2005) Nat Prod Rep
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350
300
Number of compounds/year
1965-2005
250
2006
2007
200
150
100
50
0
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Blunt et al. (2009) Nat Prod Rep 26:170-224
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Average Number of compounds/year
200
150
1965- 2007
2001- 2007
100
50
0
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Blunt et al. (2009) Nat Prod Rep 26:170-224
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Average number of compounds/year
Thai Professionals Conference 2010
1200
Total
1000
N-containing
800
600
400
200
0
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Number of patents
30
25
20
15
10
5
0
19731984
19851990
19911992
19931994
19951996
19971998
19992000
20012002
20032004
20052007
Years
Number of patents involving marine genetic resources filed between 1973-2007.
D. Leary et al (2009). Marine Policy 33: 183-194.
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Percentage of patents per category of application
D. Leary et al (2009). Marine Policy 33: 183-194.
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There is a growing recognition of the ocean’s
biotechnological potential.
The global market currently estimated at
US$ 2.4 million
10% annual growth
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The European Commission describes it as:
“one of the most exciting technology
sectors”
The Institute of Marine Engineering, Science
and Technology (IMarEST) describes the sea
as:
“biotechnological frontier waiting to be
explored”
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Major Areas of Marine Biotechnology (Blue
Technology) in EU
Food
Energy
Human Health
Environment
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Human Health
Pharmaceuticals
Nutraceuticals
Cosmeceuticals
Biomaterials
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PHARMACEUTICALS
The need for drug discovery is very important from the
perspective of global economic health.
The worldwide pharmaceutical market currently valued as € 650
billion per annum and projected to be worth € 800 billion in
2020.
The future growth rates for pharmaceuticals in developed
nations is estimated to be 5-7% per year, while in emerging
markets (BRIC), the growth rate is estimated to attain 15% per
year.
Epstein (2007) Nat. Rev. Drug. Discov
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Major areas of research in Human
Health:
Cardiovascular CV
Central Nervous System (CNS)
Anti-Infectives
Gastro-Intestinal
Cancer
Obesity, diabetes, arteriosclerosis (ODA)
The oncology sector had grown to 60b$ in 2008
New medicines are needed,
with Selective & Specific
Mechanism of Action
Bioactive Molecule
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Bioactive Molecule
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Bioactive Molecule
Drug-like Molecule
In vitro activity does not guarantee in vivo activity or good drug-like properties
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Competition for Survival &
Environmental Pressure
Biodiversity
Sea has higher biodiversity than land
Defence, Attack, Signalling
Higher Biodiversity = Higher Chemical Diversity
Chemical Diversity
Potential New Drugs
Opportunity: Marine exploration for Pharmaceutical
Purposes < 20 year old.
0.01% of terrestrial samples show anti-tumour
potential vs 1% of marine samples.
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Which are the most promising MARINE organisms as a
source of metabolites for application in human health?
Macro-organisms (mainly invertebrates)
Wide range of
chemical defenses
Industrial supply
Sponges, tunicates, corals
bryozoans, mollusks
Micro-organisms
Abundance Industrial
supply
>99% non-cultivable
Actinomycetes, fungi,
dinoflagellates, cyanobacteria
Environmental DNA (Metagenomes)
Directly to the genes
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Heterologous
expression
From non-cultivable
organisms (symbionts)
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Biodiversity to Bioactive Molecules
BioDiversity
Drug Discovery
Bioactive Molecule
Macro-Organisms
Extraction & Bio-Assay
Guided Purification
Supply
Micro-Organisms
Environmental
DNA
Bioactive molecules <10-6% wet
weight of marine organisms
Synthesis, Fermentation,
Biotechnology
Chemical structure
In Vitro Activity
Intellectual
properties
Small Quantity
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Bioactive
Molecule
Drug-like
Molecule
Metabolic stability
Medicine
Ready for
Clinical Trial
Demonstrated Quality,
Safety & Efficacy
Safety
Drug-drug PK
Drug
Toxicity
Solubility
Reaches site-of-Action
in Man (with required
concentration, duration
& safety
Absorbtion
Selectivity
MoA 1
MoA 2
Modify structure,
Drug Delivery Technology
Clinical Protocol
15-20 years
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The Drug Development Process
BioDiversity
Bioactive
Molecule
10000
100
Drug-like
Molecule
5
Discovery
Oncology
Medicine
Failures
1
III
I
Pre-clinical
Sales
Approval
II
R&D
Clinical Studies & Approval
2-10 years
3.4 years
0
4
2
6
Market
11 years
9.6 years
8
Yondelis (ET-743) : 15 years
Paclitaxel (TAXOL) : >20 years
10
12
14
16
18
From Structure Determination
(Bioactive Molecule) to FDA approval
Cost ~ $ 802 millions. Only 2 in 5 Marketed Drugs recover costs
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The supply of Marine Natural Products
The majority of Bioactive Compounds represents
<10-6 wet weight of the marine invertebrate:
1,000 g wet sponge
Drug Discovery
0.1g
Preclinical
5g
Clinical Phases
Global Market
50g
0.1 g active compound
Natural Source
Chemical Synthesis
Fermentation
Biotechnology
+ 1000 g
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Drugs from the Sea
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Early 1900s : Kainic acid
OH
O
OH
N
H
O
Kainic acid was originally isolated from the seaweed called "Kaininsou" or "Makuri" (Digenea simplex) which is used as antihelmintic in
Japan
Kainic acid is a potent central nervous system stimulant and now is
used in neuroscience research
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Early 1950s:
Bergman isolated thymine and uridine pentafuranosides
sponges (Cryptotethya crypta)
O
O
CH3
N
N
O
O
CH2OH
H
CH2OH
O
H
OH
H
OH
N
N
H
H
Spongothymidine
from air-dried
O
OH
H
H
Cryptotethya crypta
OH
H
Spongouridine
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NH2
NH2
CH2OH
H
O
H
OH
H
OH
N
O
CH2OH
H
H
Cytarabine (Ara-C)
(antitumor, 1972)
H3C
N
N
N
O
N
N
CH2OH
O
OH
H
H
H
OH
NH
H
Vidarabine (Ara-A)
(antiviral)
O
O
H
H
H
N3
H
Zidovudine (AZT)
(anti HIV) GSK
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1965: The antibiotic cephalosporin (first isolated from marine fungi)
NH2
H
N
S
N
O
HO
O
HO
O
1972: Shark cartilage oil (squalamine) inhibits angiogenesis
H3C
OSO3
CH3
CH3
+
+
NH3
N
H
H
H3C
H
+
N
H
CH3
OH
H
H
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Ziconotide (Prialt®, Elan Pharm, 2004) : the first Novel Drug from the Sea
H2N-Cys1
Lys2
A synthetic version of the N-type calcium
channel blocker ϖ −conotoxin MVIIA
H2N-Cys 25
Lys24
A peptide first isolated from the venom of
the cone snail Conus magus
Gly3
Lys4
Ala6
Gly5
Cys16
Cys15
Thr17
Lys7
Ser19
Cys8
Asp14
Tyr13
Met12
Gly23
Developed into an artificially manufactured
drug by Elan Pharmaceuticals (Ireland)
Ser9
Arg8
Leu11
Ser22
Arg21
Cys20
Approved by FDA in December 2004 and
by EU in February 2005, for the treatment
of patients suffering from chronic pain
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OMe
Yondelis® (Trabectedin, PharmaMar, Spain)
O
HO
H
N
O
H
H
O
O
approval
for
H
N
2007: approved by European Commission for
treatment of soft tissue sarcoma (STS)
2009: won final European
treatment of ovarian cancer
H
O
MeO
H
H
OH
S
NH
HO
Originally isolated from the marine tunicate
Ecteinascidia turbinata
Ecteinascidin-743 (ET-743)
The current supply is based on a semisythetic
process from safracin B, an antibiotic obtained
by fermentation of bacterium Pseudomonas
fluorescens
Ecteinascidia turbinata
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Koneni V. Sashidhara, Kimberly N. White, and Phillip Crews (2009). J Nat Prod 72:588-603
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Marine Drugs in Clinical Trials for Cancer
Mode of Action
Compound
Source
Company
Oxidative
Stress Inducer
Aplidin®
Mediterranean
Ascidian
PharmaMar
Lysosome
disturbing
Kahalalide F
Sea slug/
Alga/Bacteria
PharmaMar
Protein C
Kinase inhibitor
Bryostatin-1
Bryozoan/
Symbiont
NCI/Bristol Myers
Proteosome
inhibitor
Salinosporamide A
Marine
Bacteria
Nereus
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Big Risk for Pharmaceutical Industry
It can take as long as 15-20 years and cost as much as $800
million to develop and market a new drug.
For every 5000 novel compounds found to have biomedical
potential, an average of only five make it into clinical trials, and
only one will receive final approval for commercial patient use.
Experimental medicines are more likely to fail
than to succeed.
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NUTRACEUTICALS
Worldwide demand of
nutraceutical ingredients
are expected to reach
$21.8 billion by 2013.
ω-3 Oils
Chitin & chitosan
Glucosamine
Carotenoids
Astaxanthin
Shark Cartilage
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Algatech based in the Arava desert in Israel is
a worldwide leader in production and supply of
natural astaxanthin (antioxidant) for human
applications.
The micro-alga Haematococcus pluvialis is the
richest natural source for astaxanthin, capable
of accumulating up to 5 % of its dry biomass
Haematococcus pluvialis
O
OH
3’
3
HO
O
(3S,3’S)-Astaxanthin found in Haematococcus pluvialis and in wild salmon
Norway’s Aker Biomarine markets a range of
vitamins and nutraceuticals derived from kril and
krill by-products (e.g. Superba TM krill oil)
Krill oils are beneficial as dietary supplements for
humans as thery are rich in ω-3 fatty acids.
Meganyctiphanes norvegica
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COSMECEUTICALS
The European market for COSMETICS is booming and it is the
biggest in the world.
The trend is moving towards cosmetic natural products, in
particular those derived from plants and marine organisms.
Consumers are turning to natural and organic products as they
become aware of the possible dangers of parabens, phthalates
and other synthetic ingredients in cosmetics & toiletries.
The European natural cosmetics market continues to grow at a
healthy rate with revenues forecast o approach € 2 billion in
2010.
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Marine- based cosmetics
European Cosmetic Firms
Phytomer
Clarins
Sederma
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Marine products used in cosmetics
Bulk Chemicals – Polysaccharides
AGAR
CARRAGEENANS
FUCOIDAN
High Value Chemicals – Secondary Metabolites, Enzymes
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CLARINS
Extra-Firming Day Cream – Anti-wrinkle care for demanding skin
INGREDIENTS:
- Durvillea Antartica
Algae from Antartic are claimed to provide
resistance to pollution, central heating and
other hazards
Durvillea antarctica
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VENUCEANE™ (Sederma)
VENUCEANE™ is a biotechnological product (extremozymes) obtained
from the culture of Thermus thermophilus.
Thermus thermophilus is a thermophile bacterium (“Extremophile”) which
thrives at 80ºC and under 200 bars pressure (at a depth of 2500 meters).
Fermentation of Thermus thermophilus is possible at an industrial scale,
at a high temperature under atmospheric conditions.
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It is thermoinducible, highly thermostable and UV-stable.
It inhibits ROS and protects cells and skin from UVA damage.
Used in day creams and lotions, sun products, daily protection products,
make-up and hair care products.
Lintner et al (2009). Clinics in Dermatology
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Pseudopterosins
Diterpene pentoseglycosides isolated from the
Carribean sea Whip Pseudopterogorgia
elisabethae
Possess antiinflammatory and analgesic activities
Pseudopterogorgia elisabethae
Promote would healing (US Patent)
OH
H
Use in Skin care lotions
Ingrediente of Resilience® (Estee Lauder)
O
HO
O
OH
OH
Pseudopterosin A
Yearly income > 750,000 $
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Summary of key figures related to the value of Marine Genetic Resources
Industry
Total estimated value
of world market
Selected Product Annual Sales Value
Pharmaceutical
Industry
$643 billion in 2006
$50 m and $100 m for herpes remedy from sea
sponge (2005)
$1 billion cancer fighting agents from marine
sources (2005)
$23 million for AIDS drug Retrovir (2005)
$237 million for herpes treatment Zovirax
(2005)
Enzyme
Market
Cosmetics
Industry
Minimum of $50 billion a
year for enzymes
Estimated $150 million per year for Valley Ultra
Thin (from deep sea hydrothermal vent source)
1 billion per year for the
DNA extraction market
Estimated $20-30 million for Luminase (from
geyser)
Total $231 billion in 2005
$38.3 billion globally in
2005
for
skin
care
products
D. Leary et al (2009). Marine Policy 33: 183-194.
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Hurdles of working with Bioactive compounds
from Marine Genetic Resources
Convention on Biodiversity (CBD)/ IP Rights
United Nations Convention of Laws on the Sea (UNCLOS)
Variability of Biological Materials
Isolation of Bioactives
- Bioassay
- Repeated Rediscovery of Known Compound
- Structural Complexity
Resupply
Increase Regulation for Nutraceutical and Cosmeceuticals
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Academic –Industry Partnership
The pipelines of the major pharmaceutical companies (Big Pharma)
are shockingly depleted as they avoid the high costs and high risk of
developing new drugs.
At present, the big pharma have a desperate need to in-license
products from external sources.
This has created an opportunity for new model of academic-industry
partnership.
Academic research has traditionally been the home of research
innovation and universities offer highly skilled workforce and also
access to cost-effective infrastructure.
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Academic Drug Discovery Units (based within the universities)
These units are focused on around a scale-down pharma
model comprising of most functions required for small
molecule drug discovery
All have mixed funding models supported by research
councils and research based charities.
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Micropharma
are academia-originated, biotech startup companies that are
efficients, flexible, innovative, product-focused and small
(having less than 25, and frequently less than 10 employees)
might arise from universities, hospitals or research institutes.
They are created by 2 or 3 academic researchers who join
force to design, discover and develop new therapeutics (or
diagnostics) for human health disorders
typically focused on one or perhaps two, related diseases
Permits high-risk approaches and demonstrates
impressive capacity to absorb both success and failure
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Baden & Weaver (2010). Drug Discovery Today
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“Big Pharma”
(500+ employees)
Government-run
Laboratories
Non-governmental
Research
Organizations
“Small Pharma”
(25-500 employees)
Academic “Tech Transfer”
“Micropharma”
(<25 employees)
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The five golden goals of micropharma
1. To achieve a product (a therapeutic or diagnostic agent) that has
efficacy in a recognized animal model of a relevant human disease
2. To have insights into the mechanism of action of this agent at a
molecular and/or macromolecular level that enables rational
optimization of the agent
3. To have preliminary data pertaining to the pharmacokinetics of the
agent
4. To have preliminary data pertaining to the toxicology of the agent
5. To protect the intellectual property embodied within the agent
through a patent strategy that optimally includes composition of
matter, means of production and use
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ManRos Therapeutics (founded by Laurent Meijer
in Roscoff)
(http://www.manros-therapeutics.com)
Development of small molecule drugs against severe pathologies,
namely solid tumors, leukemia, neurodegenerative disorders.
Using a small set of disease-relevant kinases as screening targets to
identify several new families of pharmacological inhibitors.
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Present
The knowledge of Marine Genetic Resources is advancing rapidly due to:
New Technology of Diving
New Scientific Technology
(Biotechnology)
Genomics (DNA Sequencers & Bioinformatics)
Proteomics (selection & validation of targets)
Metabolomics (structure elucidation as NMR)
Industrial Applications
Pharmaceuticals
Nutraceuticals
Enzymes
Cosmetics
Others
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Metagenomic Approach: Study of Environmental DNA (or genomic DNA)
Bioactive compounds
(Peptides, Polyketides)
NRPS / PKS Enzymes
Classical
Bioprospection
DNA
(Genomic, Environmental)
Analysis of DNA
Sequences of the
Global Community
Marine samples
(organisms, sediments,
water column)
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Metagenomes: Biotechnology Applied to Marine Studies
(10L sea water or 1 g sediment or 1g sponge)
Sampling
Isolation of DNA
Cloning DNA
Metagenomic libraries
Phylogenetic Diversity
Screening
Funtional screening
Pharmaceuticals
Sequence screening
Enzymes
Piel et al (2007) App Environ Microbiol
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