Drug discoveryfrommarinesources

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Drug discoveryfrommarinesources

  1. 1. 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, INDIA15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 1
  2. 2. 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.15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 2
  3. 3. Drug Discovery Process and Productivity15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 3
  4. 4. 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 diseases15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 4
  5. 5. 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.15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 5
  6. 6. Marine Organisms15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 6
  7. 7. 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.15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 7
  8. 8. Marine Organisms for Drug Discovery• 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.15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 8
  9. 9. Marine Organisms for Drug Discovery• 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
  10. 10. 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 medicine15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 10
  11. 11. Harbor Bracnch Operates the Johnson- Prospects for SuccessSea- Link class subs Depth capability: 3000 ft 15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 11
  12. 12. Prospects for Success An Excellent View15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 12
  13. 13. A Variety of Manipulator Tools15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 13
  14. 14. Unique Work Platforms15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 14
  15. 15. How do we choose dive sites?15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 15
  16. 16. 600–800m Resolution 20-50m15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 16
  17. 17. 15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 17
  18. 18. Sensors15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 18
  19. 19. 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.15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 19
  20. 20. 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.15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 20
  21. 21. 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.15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 21
  22. 22. 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 acids15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 22
  23. 23. 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 advantage15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 23
  24. 24. Drug Discovery and Development15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 24
  25. 25. Prospects for Success15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 25
  26. 26. Marine Drug Discovery and Development15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 26
  27. 27. Marine Biodiscovery Centre15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 27
  28. 28. Sources of Chemical Diversity15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 28
  29. 29. Generating Chemical Diversity15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 29
  30. 30. Uses of Chemical Diversity15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 30
  31. 31. Screening• Purified extract library• Pure compund library• Structurally defined pure compound library15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 31
  32. 32. 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 - ICPMS15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 32
  33. 33. 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)15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 33
  34. 34. Prospects for Success Process of Marine Drug Discovery• Collection• Biological Screening• Natural Products Chemistry• Secondary Testing/Pharmacology• Production of material for clinical evaluation• Clinical investigation15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 34
  35. 35. Prospects for Success 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 Attorneys15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 35
  36. 36. Prospects for Success 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 samples15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 36
  37. 37. Prospects for Success Collection Methods1. Wading2. Scuba3. Trawling4. Submersibles15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 37
  38. 38. Prospects for Success Collection Strategies• Biological Diversity = Chemical Diversity15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 38
  39. 39. Prospects for Success Screening Approach15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 39
  40. 40. Prospects for Success 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-collaborative15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 40
  41. 41. ExtractsProspects for Success are Complex Mixtures of Marine Products15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 41
  42. 42. Prospects for Success Natural Products Chemistry• The Traditional Way15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 42
  43. 43. Prospects for Success Purification15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 43
  44. 44. Anti-tumor agents from marine sources currently licensed for developmentOrganism Metabolite Location Discoverer Current StatusBryozoan: Bryostatin I Gulf of Pettit, In PhaseBugula neritina California Arizona State I/IIclinical trials Univ. in US/Europe; NCI sponsored trials.Sea hare: Dolastatin 10 Indian Ocean Pettit, In PhaseDolabella Arizona State I/IIclinical trialsauricularia Univ. in US; NCI sponsored trials.Tunicate: Ecteinascidin Caribbean Rinehart, Univ. Licensed toEcteinascidia 743 Illinois PharmaMar S.A.turbinata In Phase II clinical trials in Europe and in US. 15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 44
  45. 45. Anti-tumor agents from marine sources currently licensed for developmentOrganism Metabolite Location Discoverer Current StatusTunicate: Dehydro-didemnin Mediterranean Rinehart, Univ Licensed toAplidium B [Aplidine] Illinois PharmaMar S.A.albicansGastropod: Kahalalide F Hawaii Scheuer, Univ. Licensed toElysia Hawaii PharmaMar S.A.rubefescensSponge: Discodermolide Caribbean Gunasekera & Licensed toDiscodermia Longley, HBOI Novartis.dissolutaSponge: Isohomo- New Zealand Munro & Blunt; Licensed toLissodendoryx halichondrin B Univ. PharmaMar S.A.sp. Canterbury, NZ 15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 45
  46. 46. Anti-tumor agents from marine sources currently licensed for developmentOrganism Metabolite Location Discoverer Current StatusActinomycete: Thiocoraline Mozambique Canedo, Spain Licensed toMicromonospora Strait PharmaMar S.A.marinaTunicate: Isogranulatimide Atlantic Andersen & Licensed toDidemnum [Brazil] Bjerinck, Univ, Kinetik, Canada.granulatum British Columbia & BrazilSponge: Bengamide Fiji Crews et al. SyntheticJaspis sp Univ. California, derivative Santa Cruz licensed to Novartis.Sponge: Hemiasterelins Papua New Andersen, Univ. Licensed toCymbastella sp. A&B Guinea British Columbia Wyeth-Ayerst. 15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 46
  47. 47. Commercially available marine bioproductsProduct Application Original Source Method of ProductionAra-A Antiviral drug Marine sponge, microbial Cryptotethya cryta fermentation of analogAra-C Anticancer drug Marine sponge, Chemical synthesis Cryptotethya cryta of analogOkadaic acid Molecular probe: Dinoflagellate Cell culture phosphatase inhibitorManoalide Molecular probe: Marine sponge, Wild harvest of phospholipase A2 Luffariella variabilis sponge inhibitor 15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 47
  48. 48. Commercially available marine bioproductsProduct Application Original Source Method of ProductionVent ® DNA Polymerase chain Deep sea Recombinant proteinpolymerase reaction enzyme hydrothermal vent bacteriumFormulaid ® Fatty acids used as Marine microalga Cell culture(Martek Biosciences, additiveColumbia, MD) in infant formula nutritional supplementAequorin Bioluminescent Bioluminescent Recombinant protein calcium indicator jellyfish, Aequora victoriaGreen Fluorescent Reporter gene Bioluminescent Recombinant proteinProtein (GFP) jellyfish, Aequora victoria 15th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 48
  49. 49. THANK YOU E-mail: bknanjwade@yahoo.co.in Cell No: 0091 974243100015th Nov. 2011 Poona College of Pharmacy, BVDU, Pune. 49

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