adrianna ianora stazione zoologica “anton dohrn” …...adrianna ianora stazione zoologica...
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Adrianna Ianora Stazione Zoologica Adrianna Ianora Stazione Zoologica ““Anton Anton DohrnDohrn”” NapoliNapoli
The Potential of Marine Microorganisms and the Use of Chemical Ecology-Derived Methods for Drug Discovery
Advantages of marine biodiversity
Current Commercial Marine Drugs
Clinical trial Name Source Target Developed byIn clinical use ectenaiscidin 743 (Yondelis) tunicate tubulin PharmaMar, RinehartPhase III E7389 (halichondrin B inspired)* synthetic tubulin EisaiPhase II dehydrodidemnin B (Aplidine) tunicate ornithine decarboxylase PharmaMar, RinehartPhase II soblidotin (aka TZT1027, dola‐10 insp.) synthetic tubulin Teikoku, PettitPhase II synthadotin (akaILX651, dola‐15 insp.) synthetic tubulin ILEXPhase II bryostatin 1 bryozoan PKC GPC Biotech, PettitPhase II squalamine shatk angiogenesis ZasloffPhase II kahalalide F mollusk multiple PharmaMar, RinehartPhase I PM02734 (kahalalide insp.) synthetic solid tumor PharmaMarPhase I Zalypsis (jorumycin insp.)* synthetic DNA PharmaMarPhase I E7974 (hemiasterlin insp.)* synthetic tubulin EisaiPhase I taltobulin (aka HTI286, hemiasterlin insp.)* synthetic tubulin Wyeth, AndersenPhase I salinosporamide A (aka NPI0052) bacteria proteasome Nereus, FenicalPhase I spisulosine (aka ES285) clam Rho PharmaMarPhase I KRN‐7000 (agelasphin insp.)* synthetic NKT Koezuka‐KirinPhase I NPI2358 (halimide insp.) synthetic tubulin Nereus, FenicalPhase I LBH589 (psammaplin insp.)* synthetic HDAC NovartisDiscontinuedPhase II <2004 dolastatin 10 sea hare tubulin PettitPhase II<1999 didemnin B tunicate antineoplastic RinehartPhase II <2004 cemadotin (dola‐15 insp.) synthetic tubulin BASF, PettitPhase II<2002 cryptophycin 52 (arenastatin)* synthetic tubulin Lilly, ValeriotePhase I<2004 discodermolide* sponge tubulin Novartis, HBOIPhase I<2002 LAF389 (bengamide insp.) synthetic MetAP Novartis, CrewsPhase I<2006 LAQ824 (psammaplin insp.) synthetic HDAC Novartis, CrewsPhase I<2000 girolline (aka girodazole)* sponge protein synthesis Potier* substances from marine sponges
Marine Drugs other than Antitumors
‐as nutritional supplements including color additives and antioxidants‐vitamins, oils, and cofactors which enhance general well‐being ‐The carotenoid market alone was projected to reach77 million Euro by 2010
Dunaliella salina
Sources of Marine Natural Products
Cultured strain of Lyngbya majuscula L. majuscula at high magnification
Colonies of a marine cyanobacterium from reefs in Papua New Guinea
Collection of filaments of a marine cyanobacterium into plastic bags
Gerwick et al. 2008
Nearly 800 compounds Have been reportedfrom marine cyanobacteria
Gerwick et al. 2008
In pre‐clinical trials
MARINE PHYTOPLANKTON AS POTENTIAL NEW DRUGS
Unicellular algae that are at the base of the marine food chain
There are more than 200 genera of living diatoms, and it is estimated that there are approximately 100,000 speciesDiatoms can be found in the oceans and in freshwater Most live pelagically in open water, although some live as surface films at the water‐sediment interface (benthic), or even under damp atmospheric conditions They are especially important in oceans, where they are estimated to contribute up to 45% of the total oceanic primary production.
Miralto et al. Nature 1999Miralto et al. Nature 1999
Oxylipin and aldehyde methabolism in diatoms
6-LOXHTrA
CO2H
H OOHCO2H
H OHCO2H
CO2HH OOH
CO2HO
CO2HH OH
6-LOX
CO2H
H OOHCO2H
H OHCO2H
CO2HH OOH
CO2HO
CO2HH OH
9-LOX
9-LOX
HTA
O
O
CO2H
CHO
CO2H
EPA11R-LOX
CO2H
HOO
CO2H
HO
12-LOX
CO2HOOH
CO2H
CO2HOH
O
OH
decatrienal
octatrienal
octadienal
C16-PUFAs
C20-PUFAs
Fontana et al. 2007Fontana et al. ChemBioChem 2007
O
OOH
OH
LOX
OH
O
CO2H
ROS
Lipolysis
Fatty acid hydroxide
Epoxy alcohol fatty acid
Polyunsaturated aldehyde
Fatty acid hydroperoxide
Fatty acid
Fontana et al. 2007
COOH
Plants
18:3ω3/18:2ω6
Blee et al. 2002
So what is the function of these metabolites?
Chemical Defense
- Noxious compounds act as feeding deterrents.
-Their main purpose would not be to intoxicate but to discourage tasting.
- Deterrence could occur after ingestion of prey cells and the predator response could be regurgitation or discouragement of further feeding
What happens if the predator feeds on toxic cells?
physical incapacitation (paralysis, altered swimming behaviour etc..) or mortality of the predator
reduction in fecundity or depressed viability of gametes
In either case, blooms grow and persist when grazing pressure would otherwise have caused them to crash
Terrestrial environmentTerrestrial environment1) Coumarins (parsley)2) Isoflavonoids (clover)3) Azadirachtin ( neem tree)4) Phytojuvenoids (sweet basil)5) Sesamin (sesame oil)6) Nicotine (tabacco)
TeratogenicTeratogenic compoundscompounds
Aquatic environmentsAquatic environments1) Aldehydes (diatoms)
Birth control effectBirth control effect
Nicotine
How do we use this chemical ecology-derived information for drug discovery?
Fontana et al. 2007
Hatching failure in the copepod Temora stylifera due to somedinoflagellate diets (Prorocentrum micans, Gymnodinium sanguinium and Gonyaulax polyedra)
Eggs stained with Hoechst 33342
Ianora et al. Limnol. Oceanogr. 1999
Harmful Algal Blooms
Saxitoxin
Alexandrium tamarense
Types of chemical ecology‐ derived bioassays :
• chemicals used to capture prey or to deter grazers• Allelopathy chemicals produced by microalgae to deter
growth of competitors• Pathogen‐host interactions• Chemicals that alter reproduction and development of
predators
We need to better foster and support the development of the new emerging field of marine chemical ecology
Proven antifeedants have been used to derive anti‐cancer, anti‐viral and anti‐agingproducts; toxins have been used to develop pain‐killers; and functional products have been obtained from the materials used by sessile organisms to colonize free surfaces.
Knowledge of eco‐physiological interactions may serve as a platform to facilitate the search for new biotechnological candidates, as well as to optimize culture conditions and achieve production of biomass for industrial applications.
More research needs to be focused on the identification of metabolites that are active in the ecological context. Once in hand the few available compounds have been drivers of intensive research efforts that have resulted in new concepts and advancements in the field.
•If we can understand the natural function of these compounds, we will be able to manage and protect them better, and find new biotechnological applications for these potentially important natural products in the future
Massimo PernaTechnician
Dott. Antonio MiraltoResp. Lab. Ecofisiologia
D.ssa Adrianna IanoraSenior Scientist
D.ssa Isabella ButtinoAssociate Scientist
D.Ssa Raffaella CasottiAssociate Scientist
Andrea Gerecht PhD student
D.SsaGiovanna RomanoAssociate Scientist
Mario Di PintoTechnician
Dott. Francesco EspositoTechnologist Vittoria Roncalli
MSc student
D.ssa Ylenia CarotenutoAssociate Scientist
Flora PalumboTechnician
Francois RibaletPhD student
Cecilia Balestra Phd student
CNR Istituto di Chimica Biomoleculare
CNR-ICBAngelo FontanaAdele “Lella” CutignanoGiuliana d’IppolitoNadia LamariAntonio MaielloGuido Cimino
CNR-ISAGianluca Picariello
CNR-IBPNando Febbraio