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Marine Pharmaceuticals
- 1. Marine Pharmaceuticals Drugs from the Deep Presented by: Justin Porter BIOL 4320H Winter 2012
- 2. Why look to the Sea? • Biodiversity and evolution of unique defensive compounds • Approx. 11,000 marine compared to 155,000 terrestrial derived drugs • New treatments for MDR • Low toxic side effects
- 3. Diving into marine drug development • Properties discovered: •Anti-bacterial •Anti-coagulant •Anti-fungal •Anti-protozoal •Anti-tuberculosis •Anti-viral
- 4. Sponges
- 5. Sponges • Anti-viral: •Currently on the market •Acyclovir •Ara-A (vidarabine) •Ara-C (cytarabine) •In development •4-methylaaptamine •EC50 = 2.4 µM •Verongiaquinol
- 6. Sponges (continued) • Anti-bacterial & Anti-fungal: •Verongiaquinol •MIC = 8 µg/mL •Manzamine A •Broad-spectrum vs Gram-positive •Good vs Gram-negative •Verongiaquinol and Manzamine A are very effective antifungal agents.
- 7. Sponges (continued) • Anti-protozoal & Anti-tuberculosis: •Xestoquinone •Anti-malarial polyketide •Pfnek-1 kinase inhibition •IC50 = 1.1 µM to 3 µM •Manzamine Alkaloids •Inhibit M. tuberculosis •IC50 = 0.4 µg/mL to 5.2 µg/mL •6-hydroxymanzamine E is most potent
- 9. Marine Fungi
- 10. Fungi • Anti-viral & Anti-bacterial: •Halovirs A-E •Linear peptides from Scytidium spp. •Halovir A Inhibits HSV-1 and HSV-2 •EC50 = 280 nM •Corollosporine •Antibacterial metabolite •Isolated from Corollospora maritime
- 11. Algae
- 12. Algae • Anti-viral: •Most antiviral compounds from marine algae are polysaccharides •Diterpenes from Dictyota spp. •Inhibit HIV-1 reverse transcriptase •Dolabelladienetriol •Terpenoid from Sargassum binderi •Non-competitive inhibitor of HIV-1 RT
- 13. Algae (continued) • Anti-inflammatory & Anti-fungal: •Fucoxanthin •Pigment from Myagropsis myagorides •Anti-inflammatory effect rivals the current SAID predinisolone! •Extracts from Odonthalia corymbifera •Potent inhibition of fungal Isocitrate Lysase •IC50 = 23 µg/mL •May be effective against Candida albicans
- 14. Fish
- 15. Fish Anti-bacterial Properties • Innate antimicrobial arsenal of complements, lectins and lysozymes in the mucus and serum • Acidic glycoprotien L-amino acid oxidase (LAO) was isolated from Rockfish (Sebastes schlegelii) •Specifically catalyzes L-lysine •Induces damage and morphological changes to bacterial cell surface
- 16. Fish (continued) Anti-coagulant Properties •Monomeric protein isolated from Yellowfin sole (Limanda aspera) inhibited serine endopeptidase factor XII •Controls platelet aggregation by creating an inactive complex
- 17. Corals
- 18. Corals • Anti-inflammatory: •Pseudopterosin A •Diterpene glycoside from Pseudopterogorgia elisabethae (Caribbean Sea Whip) •Anti-inflammatory effect rivals industry standards •Used in some Estée Lauder cosmetics
- 20. • Many promising compounds in preclinical stages: •TGAP •Anticoagulant polypeptide from Tegillarca granosa (Malaysian cockle) •Inhibits conversion of prothrombin to thrombin
- 21. Future of Marine Pharmaceuticals • Challenges: •Accessibility •Rarity •Endangered or protected species and their products require cumbersome permitting procedures •Large-scale production •Chemical synthesis may be a solution for some •Acyclovir •Cultivation using bioreactors •Combinatorial biosynthesis •There are many more discoveries to be made!
- 22. Conclusions
- 23. References Aqil, F., M. Zahin, K.A. El Sayed, I. Ahmad, K.Y. Orabi, and J.M. Kijjoa A. and P. Sawangwong. 2004. Drugs and Cosmetics Arif. 2011. Antimicrobial antioxidant, and anitmutagenic from the Sea. Mar. Drugs. 2: 73-82. activities of selected marine natural products and Kitani Y., N. Kikuchi, G. Zhang, S. Ishizaki, K. Shimakura, K. tobacco cembranoids. Drug and Chemical Toxicology, Shiomi and Y. Nagashima. 2008. Antibacterial action of 24(2): 167-179. L-amino acid oxidase from the skin mucus of rockfish Berrue, F., O.P. Thomas, R. Laville, S. Prado, J. Golebiowski, R. Sebastes schlegelii. CBP Part B: Biochemistry and Fernandez, and P. Amade. 2007. The marine sponge Molecular Biology. 149( 2): 394-400. Plakortis zyggompha: a source of original bioactive Larghi, E.L., M.L. Bohn, and T.S. Kaufman. 2009. Aaptamine polyketides. Tetrahedron. 63: 2328-2334. and related products. Their isolation, chemical De Souza Pereira H., L.R. Leaso-Ferreira, N. Moussatche, V.L. syntheses, and biological activity. Tetrahedron, 65: Telixeira , D.N. Cavalcanti, L.J. Da Costa and I.C. 4257-4282. Fruulhetti. 2005. Effects of diterpenses isolated from Leary, D., M. Vierros, G. Hamon, S, Arico and C. Monagle. the Brazilian marine alga Dictyota menstrualis on HIV-1 2009. Marine genetic resources: A review of scientific reverse transcriptase. Planta Med. 71(11): 1019-24. and commercial interest. Marine Policy, 33: 183-194. El-Amraoui, B., J.F. Biard, M.J. Uriz, S. Rifai, and A. Fassouane. Lee, J.B. , K. Hayashi, M. Hirata, E. Kuroda, E. Suzuki, Y. Kubo, 2010. Antifungal and antibacterial activity of Porifera and T. Hayashi. 2006. Antiviral sulfated polysaccharide extracts from the Moroccan Atlantic coasts. Journal de from Navicula directa, a diatom collected from deep- Mycologie Médicale. 20: 70-74. seawater in Toyama Bay, Biol. Pharm. Bull. 29: 2135– Imhoff, J.F., A. Labes, and J. Wiese. 2011. Bio-mining the 2139. microbial treasures of the ocean: New natural products. Mayer, A.M.S, A.D. Rodriguez, R.G.S. Berlinck and M.T. Biotechnology Advances. 29: 468-482. Hamann. 2009. Marine pharmacology in 2005-6: Jacquet, S., T. Miki, R. Noble, P. Peduzzi and S. Wilhelm. Marine compounds with anthelmintic, antibacterial, 2010. Viruses in aquatic ecosystems: important anticoagulant, antifungal, anti-inflammatory, advancements of the last 20 years and prospects for the antimalarial, antiprotozoal, antituberculosis an antiviral future in the field of microbial oceanography and activies; affecting the cardiovascular, immune and limnology. Advances in Oceanography and Limnology, nervous systems, and other miscellaneous mechanisms 1(1): 97-141. of action. Biochima et Biophysica Acta, 1790: 283-308.
- 24. References (continued) Mayer A.M.S., A.D. Rodriguez, R.G.S. Berlinck and N. Fusetani. Subramanian, S., N.W. Ross and S.L. Mackinnon. 2008. 2011. Marine pharmacology in 2007-8: Marine Comparison of antimicrobial activity in the epidermal compounds with antibacterial, anticoagulant, mucus extracts of fish. CBP Part B: Biochemisty and antifungal, anti-inflammatory, antimalarial, Molecular Biology, 150(1): 85-92 antiprotozoal, antitberculosis and antiviral activities: Villa, F.A. and L. Gerwick. 2010. Marine natural products affecting the immune and nervous system, and other discovery: Leads for treatment of inflammation, cancer, miscellaneous mechanisms of action. Comparative infections, and neurological disorders. Biochemistry and Physiology, Part C. 153: 191-222. Immunopharmacology and Immunotoxicology, 32(2): Pangestuti R. and S. Kim. 2011. Biological activities and 228-237. health benefit effects of natural pigments derived from Vo, T., D. Ngo, Q.V. Ta and S. Kim. 2011. Marine organisms as marine algae. Journal of Functional Foods, 3:255-266. a therapeutic source against herpes simplex virus Qi S.H., S. Zhang, L.H. Yang and Qian P.Y. 2008. Antifouling infection. European Journal of Pharmaceutical Science, and antibacterial compounds from the gorgians 44: 11-20. Subergorgia gracillis. Natural Products Research, 22 (2): Wase, N.V. and P.C. Wright. 2008. Systems biology of 154-166 cyanobacterial secondary metabolite production and its Rastogi, R.P. and R.P. Sinha. 2009. Biotechnological and role in drug discovery. Expert Opin. Drug Discov., 3(8): industrial significance of cyanobacterial secondary 903-929. metabolites. Biotechnology Advances, 27: 521-539. Wiliams, P.G. 2008. Planning for chemical gold: marine Sperstad S.V., T. Haug, H. Blencke, O.B. Styrvoid, C. Li and K. bacteria as a source of new therapeutics. Trends in Stensvag. 2011. Antimicrobial peptides from marine Biotechnology, 27(1): 45-52. invertebrates: Chanllenges and perspectives in marine Uzair B., Z. Mahmood and S. Tabassum., 2011. Antiviral antimicrobial peptide discovery. Biotechnology activity of natural products extracted from Marine Advances. 29: 519-530. organisms. BioImpacts 1(4): 203-211. Stengel, D.B., S. Connan and Z.A. Popper. 2011. Algal Yasuhara-Bell, J. and Y. Lu. 2010. Marine compounds and chemodiversity and bioactivity: Sources of natural their antiviral activities. Antiviral Research, 66: 231-240 variability and implications for commercial application. Biotechnology Advances, 29: 483-501.
- 25. References (continued) Mayer A.M.S., A.D. Rodriguez, R.G.S. Berlinck and N. Fusetani. Subramanian, S., N.W. Ross and S.L. Mackinnon. 2008. 2011. Marine pharmacology in 2007-8: Marine Comparison of antimicrobial activity in the epidermal compounds with antibacterial, anticoagulant, mucus extracts of fish. CBP Part B: Biochemisty and antifungal, anti-inflammatory, antimalarial, Molecular Biology, 150(1): 85-92 antiprotozoal, antitberculosis and antiviral activities: Villa, F.A. and L. Gerwick. 2010. Marine natural products affecting the immune and nervous system, and other discovery: Leads for treatment of inflammation, cancer, miscellaneous mechanisms of action. Comparative infections, and neurological disorders. Biochemistry and Physiology, Part C. 153: 191-222. Immunopharmacology and Immunotoxicology, 32(2): Pangestuti R. and S. Kim. 2011. Biological activities and 228-237. health benefit effects of natural pigments derived from Vo, T., D. Ngo, Q.V. Ta and S. Kim. 2011. Marine organisms as marine algae. Journal of Functional Foods, 3:255-266. a therapeutic source against herpes simplex virus Qi S.H., S. Zhang, L.H. Yang and Qian P.Y. 2008. Antifouling infection. European Journal of Pharmaceutical Science, and antibacterial compounds from the gorgians 44: 11-20. Subergorgia gracillis. Natural Products Research, 22 (2): Wase, N.V. and P.C. Wright. 2008. Systems biology of 154-166 cyanobacterial secondary metabolite production and its Rastogi, R.P. and R.P. Sinha. 2009. Biotechnological and role in drug discovery. Expert Opin. Drug Discov., 3(8): industrial significance of cyanobacterial secondary 903-929. metabolites. Biotechnology Advances, 27: 521-539. Wiliams, P.G. 2008. Planning for chemical gold: marine Sperstad S.V., T. Haug, H. Blencke, O.B. Styrvoid, C. Li and K. bacteria as a source of new therapeutics. Trends in Stensvag. 2011. Antimicrobial peptides from marine Biotechnology, 27(1): 45-52. invertebrates: Chanllenges and perspectives in marine Uzair B., Z. Mahmood and S. Tabassum., 2011. Antiviral antimicrobial peptide discovery. Biotechnology activity of natural products extracted from Marine Advances. 29: 519-530. organisms. BioImpacts 1(4): 203-211. Stengel, D.B., S. Connan and Z.A. Popper. 2011. Algal Yasuhara-Bell, J. and Y. Lu. 2010. Marine compounds and chemodiversity and bioactivity: Sources of natural their antiviral activities. Antiviral Research, 66: 231-240 variability and implications for commercial application. Biotechnology Advances, 29: 483-501.
- 26. QUESTIONS?
Notas do Editor
- Anti-bacterial Anti-coagulant Anti-fungal Anti-inflammatory Anti-protozoal Anti-tuberculosis Anti-viral
- Marine Environment = ~1/2 of global biodiversity ( Sperstad et al. , 2011; Vo et al ., 2011; Yasuhara-Bell and Lu, 2010) Oceans contain 34 of the 36 phyla ~300,000 described species (small % of what is out there, since only about 3% of ocean has been explored) Estimated between 3 million and 500 million species Coral reefs alone rival the biodiversity of tropical rainforests Deep sea hydrothermal vents Abyssal plain (not barren) Plankton (global) Many extreme environments --> novel compounds The sea is rich in Biodiversity and having to live under extreme conditions has resulted in the evolution of very unique defences to survive. Marine Pharmaceuticals are in their infancy compared to terrestrial Pharmaceuticals. about 11,000 marine derived pharmaceuticals compared to 155,000 terrestrial products. (2009) The search for new drugs, therapeutic agents and natural products is crucial, especially with the rise of antibiotic resistant and multi-drug resistant (MDR) bacteria, fungi, protozoa and viruses To improve the medicine and treatment of ailments with compounds that have low toxic side effects. Example fungicides and anti-mycobaterial for tuberculosis treatments very toxic and take 6-9months of use.
- It all started with sponges in 1959. In 1959, was the first study of sponges producing antimicrobial substances. Since then there has been a boom in marine exploration for new chemical compounds used to combat infectious diseases Exploration of numerous species of sponges, fungi, fish, bacteria, algae and other invertebrates compounds that have shown anti-bacterial, anti-coagulant, anti-fungal, anti-inflammatory, anti-protozoal, anti-tuberculosis and anti-viral properties
- There have been more than 15,000 products derived from more than 5,300 different compounds from marine sponges (Vo et al. , 2011; Yasuhara-Bell and Lu, 2010). It is no surprise that sponges are a significant source of pharmacologically active agents, given their location and role in the marine environment Sponges (Porifera) are benthic stationary filter feeding organisms that "clean" the marine environment
- Anti-Viral: Many antiviral agents have been derived from marine sponges Currently on the market: Acyclovir - Synthetic derivative of arabinosyl nucleosides from sponge, Tethya cripta - HSV Inhibits HSV-1 replication EC50 = 8.6 µM Ara-A (vidarabine) /Ara-C (cytarabine) - HSV Alkaloid - 4-methylaaptamine from sponge Aaptos aaptos Inhibits HSV-1 replication EC50 = 2.4 µM (Better than acyclovir!) Verongiaquinol (Aquil et al. , 2011) Anti-HIV-1 activity (ED50 = 6.1 µM)
- Anti-Bacterial : (Aquil et al. , 2011) Over 800 antibacterial compounds have been isolated from sponges (El-Amraoui et al. , 2010) Verongioquinol from Red Sea sponge Aplysina spp. (minimum IC = 8 µg/mL) Manzamine A from Indo-Pacific Acanthostrongylophora spp. Manzamines are polycyclic alkaloids Very promising Has shown broad-spectrum activity vs Gram-positive bacteria Moderate-good activity vs Gram-negative bacteria Anti- Fungal: Verongioquinol and Manzamine A
- Anti-Protozoal (Gutiérrez et al. , 2005; Kaur et al. , 2009; Mayer et al ., 2009) Parasitic diseases: Malaria ( Plasmodium falciparum ), leishmaniasis, Chagas disease (Trypanosoma cruzi ) , dengue fever Xestoquinone is polyketide anti-malarial agent from Xestospongia spp. Pfnek-1 kinase inhibition (IC 50 = 1.1 µM to 3 µM) P. falciparum NIMA (never-in-mitosis)-related kinase. – Prevents asexual reproduction Anti-Tuberculosis [ Mycobacterium tuberculosis ] ( Berrué et al. , 2007; Mayer et al. , 2009; Mayer et al. , 2011) No known mechanisms of antimycobacterial action for marine compounds. Manzamine Alkaloids (Kishore et al. , 2009; Rao et al. , 2006) Inhibits M. tuberculosis with IC50 = 0.4-5.2 µg/mL 6-hydroxymanzamine E (IC50 = 0.4 µg/mL) Manzamine A (IC50 = 1.5 µg/mL) Manzamine F (IC50 = 2.6 µg/mL) Manzamine E (IC50 = 3.8 µg/mL) Manzamine Y (IC50 = 5.2 µg/mL) Spiculoic Acids (Berrué et al. , 2007) 24-Norisospiculoic acid A - antimycobacterial effect on M. tuberculosis with minimum IC99 = 50 µg/mL
- Many bacterial species permanently inhabit sponges as symbionts. In some cases, associated bacteria might be the producers of the isolated pharmaceutically active compounds from sponges.
- Marine fungi have been found with: Antiviral antibacterial Antifungal properties (Vo et al. , 2011; Yasuhara-Bell and Lu, 2011)
- Antiviral Linear peptides - Halovirs A-E isolated from marine fungus Scytidium spp. Halovir A inhibits HSV-1 and HSV-2 with EC50 = 280 nM in standard plaque reduction assay Render HSV non-infectious by membrane destabilisation (Vo et al. , 2011) Antibacterial Corollosporine - antibacterial metabolite from Corollospora maritime (Yasuhara-Bell and Lu, 2011).
- Marine algae: Macroalgae - Seaweeds (red, brown, green algae) Microalgae - Phytoplankton - Dinoflagellates, red, brown, green, blue-green algae (cyanobacteria), diatoms
- Dictyota = Brown algae (macroalgae) Sargassum binderi = Brown macroalgae
- Anti-inflammatory Pigment - Fucoxanthin from Myagropsis myagroides (Pangestuti and Kim, 2011) Anti-inflammatory effect rivals the current steroidal anti-inflammatory drug (SAID) predinisolone Antifungal: Odonthalia corymbifera (Lee et al. , 2007) Red macroalga. Inhibits fungal Isocitrate Lysase required for glyoxylate cycle Most dangerous human pathogenic fungus = Candida albicans Potent inhibition of ICL (IC50 = 23 µg/mL)
- The Mucus and serum found on fish serve as a fish’s first line of defence against pathogens. Recently, there has been great interest in fish as a source for novel bacterialcides Studies on the mucus extracts exhibit inhibition of microbial activity for both fish and human pathogens (Subramanian et al. 2008) e.g. salmonella. Mucus extracts were taken from haddock, arctic Char, hagfish and brook trout. Isolated from the Serum of rockfish was 120kDa acidic glycoprotein L-amino acid oxidase (LAO). Which selectively targeted and inhibited gram-negative bacteria (MIC=0.078-0.63 µg/mL). Using an electron microscope it was found that the protein induced damage and morphological changes to the surface of the bacterial cells. The effectiveness of the antibacterial action was controlled by H 2 O 2. (Mayer et al. 2011). LAO specifically catalyzes L-lysine with a K m 0.37 mM and k cat 57.1 s − 1 serum LAO exhibited antibacterial activity potently against Aeromonas hydrophila and Aeromonas salmonicida, which are disease associated with Cholera in infants and children with compromised immune systems, but it is commonly a persistent disease for amphibians, fish and reptiles. Commonly known by fish enthusiasts as Fin and Tail Rot. Very promising results for a novel agent especially for aquariums and veterinary Medicine.
- -In the marine yellowfin sole ( Limanda aspera ) was discovered a 12.01 kDa single-chain monomeric protein which inhibited the blood coagulation serine endopeptidase factor XII. -It accomplishes this by creating an inactive complex by binding to a membrane glycoprotein intergrin, which stimulates platelet aggregation.
- Corals are Cnidarians Relatives of jellyfish and sea anemones
- Anti-inflammatory - Pseudopterosin A from Pseudopterogorgia elisabethae [Gorgonian soft coral, Octocoral] Has been used by Estée Lauder in cosmetic products
- Molluscs - Clams, mussels, oysters, abalone, snails, cephalopods
- Molluscs - Clams, mussels, oysters, abalone, snails, sea slugs, cephalopods) Crustaceans Echinoderms – Sea urchins, sea stars, brittle stars, sea cucumbers, sand dollars T. granosa Anti-coagulant polypeptide (TGAP) from Bivalve ( Tegillarca granosa ) “Malaysian cockle” or “Granulated ark” Inhibition of prothrombin (factor II) to thrombin ( IIa) conversion IC 50 = 77.9 nM Specific binding to factor Va and prothrombin (factor II)
- Compare Pros and cons of Marine pharmaceuticals Challenges Large-scale production Chemical synthesis may be a solution for some e.g. Acyclovir Cultivation using bioreactors Combinatorial biosynthesis