MARINE BIOTECHNOLOGY : BIOACTIVE NATURAL PRODUCTS AND THEIR APPLICATIONS

 

Trivesh S. Mayekar, Amod A. Salgaonkar, J.M.Koli, Pravin Patil, Ajit Chaudhari, Anup Murkar*, Sameer Salvi*, Devendra Surve*, Rakesh Jadhav*, Tousif kazi*.

Central Institute of Fisheries Education, Seven Bungalow, Versova, Mumbai-400061

*College of Fisheries, Ratnagiri

Corresponding author E-mail: mayekartrivesh@gmail.com

 

 

Introduction

 

Marine (or blue) biotechnology encompasses the applications of biotechnology tools on marine resources. Marine biotechnology encompasses those efforts that involve the marine resources of the world, either as the source or target of biotechnology applications. Biotechnology is the application of science and technology to living organisms, as well as parts, products and models thereof, to alter living or non-living materials for the production of knowledge, goods and services'. In the case of marine biotechnology, the living organisms derive from marine sources. Biotechnology is defined as the industrial use of living organisms or biological techniques developed through basic research; marine biotechnology is an emerging discipline based on the use of marine natural resources. The oceans encompass about 71% of the surface of our planet, but over 99% of the biosphere (since organisms are found throughout the water column), and they represent the greatest extremes of temperature, light, and pressure encountered by life. Adaptation to these harsh environments has led to a rich marine bio- and genetic-diversity with potential biotechnological applications related to drug discovery, environmental remediation, increasing seafood supply and safety, and developing new resources and industrial processes.

 

Drug discovery represents one of the most promising and highly visible outcomes of marine biotechnology research. Biochemicals produced by marine invertebrates, algae and bacteria, are very different than those from related terrestrial organisms and thus offer great potential as new classes of medicines. To date, examples of marine-derived drugs include an antibiotic from a fungi, two closely related compounds from a sponge that treat cancer and the herpes virus, and a neurotoxin from a snail that has painkiller properties making it 10,000 times more potent than morphine without the side effects. However, there are several more marine-derived compounds currently in clinical trials and it is likely that many more will advance to the clinic as more scientists look to the sea for these biotechnological uses. In addition to new medicines, other uses for marine-derived compounds include: cosmetics (algae, crustacean and sea fan compounds), nutritional supplements (algae and fish compounds), artificial bone (corals), and industrial applications (fluorescent compounds from jellyfish, novel glues from mussels, and heat resistant enzymes from deep-sea bacteria).

 

Marine biotechnology may include techniques such as bioprocessing, bioharvesting, bioprospecting, bioremediation, using bioreactors etc (so called process biotechnology techniques); aquaculture/fisheries; gene, protein, or other molecule based techniques; while applications may include: health, food, cosmetics, aquaculture & agriculture, fisheries, manufacturing, environmental remediation, biofilms and corrosion, biomaterials, research tools etc. Therefore, marine biotechnology has a horizontal scope encompassing very different applications, for all of which the marine environment is providing the resources. This means everything from deriving a new cancer treatment from a deep-sea sponge to developing an innovative buoy system for monitoring ocean pollution. Like the broader field of biotechnology, marine biotechnology (marine biotech or MBT) can take very traditional forms, such as localized seaweed farming, and high-tech forms. The full range of genomic tools, for instance, is now being applied to such goals as determining precisely how a promising compound derived from a marine organism kills cancer cells. Commercial applications of marine biotechnology includes bio-prospecting, improving the production of marine organisms, production of novel products, particularly food and feed products and diagnostics and biosensors. Bioprospecting includes biotechnology use in whole drug/molecule development process, i.e. screening, identification, efficacy testing, safety testing, large scale commercial production. Bioactive natural products are secondary metabolites produced by organisms that live in the sea. These products have received increasing attention  from chemists and pharmacologists during the last two decades. These products have been exploited for variety of purposes including use as food, fragrances, pigments, insecticides and medicines. Through improved biological screening method the role of these products in drug discovery has been greatly enhanced in the last few years. These products show an interesting array of diverse and novel chemical structures with potent biological activities.

 

Research into pharmacological properties of marine natural products has led to the discovery of many compounds considered worthy of clinical applications.There are great potential in bioprospecting from the sea and marine natural products research has just started to bloom.Today, marine sources have the highest probability of yielding natural products with unprecedented carbon skeletons and interesting biological activities.Many more prospects  regarding new habitats for example deep ocean samplesand symbiotic systems are still wide open for research.

 

Bioprospecting

 

It is high-throughput screening for novel compounds, especially drugs (other uses includes in foodstuffs, nutraceuticals, adhesives, paints, cosmetics, environmental remediation, research etc). It includes biotechnology use in whole drug/molecule development process, i.e. screening, identification, efficacy testing, safety testing, large scale commercial production. Traditionally only 1 out of 10,000-20,000 molecules extracted from terrestrial micro-organisms, plants or animals finally reached the market, which may take 10-15 years and cost up to $800m12,13. This has resulted in large pharmaceutical groups abandoning their search for new drugs derived from natural substances. Evidence of complexity in this process is the relatively empty pipeline of pharmaceutical companies. However, marine biota present a better opportunity for encountering successful candidates in view of the large biodiversity, lack of current knowledge and extreme environments. Ara-C and Ara-A (estimated annual worth $50-100 million) drugs were developed from sponges in the early 50s and proved to be commercial success stories. Anti-cancer agents from marine organisms have an estimated value of $1 billion a year. Another good example includes Vent-DNA polymerase which is used as a basic constituent in Polymerase Chain Reaction (PCR). Bioprospecting is applied to all animal and plant phyla living in shallow as well as in deep seabed ecosystems. The advantages of the first include less technical complexity and better economic viability whereas for the latter a larger and perhaps more interesting natural resource base. In general, it is thought that the pace of discovery of new species and products that are potentially useful to pharmacology is higher for marine and microbial than for terrestrial organisms.

 

Marine bioprospecting: Mining the untapped potential of living marine resources

 

Compared to the high degree of representation of terrestrial-derived bioproducts, the number of marine natural products that have found their way into hospitals, clinics and pharmacies is thus far small. This has more to do with the relative infancy of the field (compared to terrestrial bioprospecting) than any lack of potential for discovery. In fact, the natural products isolated from marine sources tend to be more highly bioactive than terrestrial counterparts. This is in part because they have to retain their potency despite dilution in surrounding seawater to be effective in the "chemical warfare" that allows organisms such as sponges to ward off would-be predators and animals that might attempt to grow over and smother them. Despite lesser attention paid to marine natural products historically, there are notable marine-derived bio products that are commercially available, including:

•   The family of antiviral drug, including Aids treatment AZT, based on a group of compounds (arabinosides) extracted from the sponge Tethya crypta more than 40 years ago. This success story from marine biomedicine's first wave represents an annual market of more than $50 million.
•   The anti-inflamatory and analgesic pseudopterosins isolated from a Bahamian soft coral (Pseudoterigorgia elisabethae). This led to the development of bioproducts now used in Estee Lauder skin care and cosmetics lines and currently worth $3-4 million a year.
•   Ziconitide, known by its trade name Prialt¨ is a synthetic form of a compound extracted from the venom of predatory tropical cone snails (Conus spp.). Prialt¬ was approved by the FDA in late 2004 as a treatment for severe cases of chronic pain in patients with conditions such as cancer and AIDS. Current clinical results suggest that Prialt is a powerful, non-addictive alternative to drugs such as morphine

Easily overlooked in the success stories is the technical difficulty of collecting and processing diverse marine organisms, screening them for bioactivity, isolating and identifying natural products, securing a sustainable source of the product, and various other hurdles on the path toward developing a potentially profitable bioproduct. There is a substantial cost associated with each stage of the endeavor. Furthermore, even when no expense is spared, and even if the best and brightest researchers are on the job, there is never a guarantee that the effort will pan out, but the vast potential payoffs, not only financially through potential commercial sales but also at the human level in lives potentially saved or improved, keeps the field moving forward. Marine bioprospecting is often used to describe the process of collecting marine biota for natural product screening. Of course, biomedical MBT investigations are usually carried out by large research institutions and consortiums and not private individuals, so when a drug lead doesn't 'pan out,' personal financial ruin is not typically the result. Still, the fact that only a handful of the 10,000 or so novel chemical compounds thus far isolated from marine organisms have made their way into the drug discovery pipeline says something about the chances of any one compound ever making its way to the drug market. Moreover, of those compounds that do enter the clinical development pipeline, a large number eventually are discarded to the biomedical boneyard.As an indication of the investment involved in marine bioprospecting, consider that the UN Atlas of the Oceans reports Japan on its own spends nearly $1 billion on such efforts. Of this sizeable figure, 80% is funded through the private sector.

Specimen Acquisition

A 'typical' marine biotechnology natural products research group will have research objectives centered on any and/or all of the following:

•   Collection of marine organisms with promising or as yet unstudied bioactivity
•   Detection of bioactivity
•   Isolation and identification of bioactive compounds
•   Evaluation of the pharmaceutical or other potential of novel compounds

The collection of marine organisms allows assessment of their biomedical or biotechnology potential. The collecting (prospecting) phase of the research is, by definition, a field-based endeavor. The follow-on biotechnology assessment phase is then carried out back in the laboratory in the days, weeks, months, and even years following initial collection.

Collection techniques include:

•   Traditional snorkel and SCUBA
•    Ship-based collection via bottles, nets, trawls, and benthic grabs, sleds, and dredges
•   Collection via ROVs (Remotely Opertated Vehicles) and AUVs (Autonomous Underwhater Vehicles)
•   Submersible-based collection

Important bioactive compounds and their applications :

 

Molluscan Derived Compounds

 

Dolastatins

 

Dolastatin 10 and dolastatin 15 were isolated from the Indian Ocean sea hare Dollabella auricularia. These small linear peptide molecules are promising anti-cancer drugs showing potency against breast and liver cancers, solid tumors and some leukemias. Preclinical research indicated potency in experimental antineoplastic and tubulin assembly systems. The dolastatins are mitotic inhibitors. They interfere with tubulin formation and thereby disrupt cell division by mitosis.

 

 

Kahalaide F

 

Kahalalide F was isolated from a sacoglossan (sea slug) mollusc, Elysia rufescens, collected from Hawaii. Kahalalide F appears capable of disrupting lysosome membranes within certain target cells, thereby initiating apoptosis (programmed cell death). The drug also appears to inhibit the expression of certain specific genes that are involved in DNA replication and cell proliferation, thereby inhibiting tumor spreading and growth.

 

Spisulosine

 

Isolation of this natural product from the commercially harvested Arctic surf clam Spisula (=Mactromeris) polynyma by researchers from the Spanish PharmaMar group was first reported in 1999. The molecule shows promise as an antiproliferative (anti-tumor) agent, and has intriguing mechanism of action.

 

Ziconotide (Prialt¨)

 

Ziconotide is a synthetic derivative of short (25 amino acid) peptide extracted from the venom of predatory cone snails (Conus geographicus, Conus magus). This drug, a member of a newly described chemical family called the conopeptides, is a generating a lot of interest as a potential pain management drug. Results from clinical trials to date have suggested ziconotide's effectiveness in treating pain may be from fifty to several thousand times better than that of morphine. The fact that ziconotide and other conotoxins are short (usually 20-30 amino acids) means that synthetic derivatives are typically easy to produce. A synthetic version of the drug, SNX-111, is manufactured by licensee Elan Corporation under the trade name Prialt¨.

 

CadalminTM Green Mussel Extract (GMe)

 

CMFRI was developed new product CadalminTM Green Mussel Extract (GMe) to combat arthritis.CadalminTM. GMe contains 100% natural marine bioactive anti-inflammatory ingredients extracted from green mussel Perna viridis. The product is effective to combat chronic joint pain, arthritis/ inflammatory diseases, and improves cardiovascular functioning. It is an effective green alternative to synthetic non steroidal anti-inflammatory drugs (viz., aspirin containing drugs having undesirable side effects). The active principle in CadalminTM GMe effectively inhibits inflammatory cyclooxygenase-II and lipoxygenase-V, and its activity was found to be comparable to the drugs available in the market. Consuming CadalminTM GMe will avoid unfortunate side effect of these synthetic non steroidal anti-inflammatory drugs. This product is a blend of nutraceutical and nutritional elements. CadalminTM GMe is designed to find a unique way to prevent the degradation by air, moisture, heat and light and to maximize the activity. The product is free from deleterious trans fatty acids, free radicals/free radical adducts, and low molecular weight carbonyl compounds.

 

Vertebrate-Derived Compounds

 

Squalamine

 

Squalamine is an aminosterol isolated from the stomach and liver of the spiny dogfish, Squalus acanthus, a common New England coastal shark species. 
When it was discovered in 1993, the compound was reported to exhibit broad-spectrum antibiotic activity. Squalamine was licensed to Magainin Pharmaceuticals (now Genaera Corporation) for development. Of considerable interest is published evidence suggesting that squalamine exhibits anti-angiogenic activity under certain conditions (angiogenesis is the formation and differentiation of blood vessels).

 

Neovastat" (AE-941)

 

Neovastat (AE-941) is a derivative of shark cartilage extract. Rather than being a specific monomolecular compound, AE-941 is a defined standardized liquid extract comprising the < 500 kDa (kilodaltons, a unit of mass) fraction from shark cartilage.  It has the anti-angiogenic and antitumor activity. The drug's anti-angiogenic bioactivity suggests it could be a valuable agent for use in patients suffering from multiple myeloma and other hematologic (blood) diseases.

 

 

Sponge-Derived Compounds

 

Bengamides and Derivatives

 

Two novel seven-membered ring heterocycles, bengamide A and bengamide B, were reported in 1986 isolated from an as yet undescribed Fijian sponge belonging to family Jaspidae. Since this time, a number of additional compounds from the bengamide class have been isolated, most notably from the Fijian sponge Jaspiscf. coriacea. Bengamides A and B were initially reported to exhibit in vitro toxicity to larynx epithelial carcinoma cells, and to have antibiotic and anti-helminthic activity (against the nematode Nippostrongulus braziliensis).

 

Contignasterol (IZP-94005, IPL576,092)

 

Contignasterol (IZP-94005) from the sponge Petrosia contignata was first reported in the early 1990s. The natural compound itself was deemed a good anti-asthma drug candidate based on performance in in vivo animal models. One contignasterol derivative, named IPL576,092, shows promise as an oral asthma medication. More recently, IPL576,092 has entered clinical trials as a treatment for diseases causing inflammation of the eyes and skin.

 

Debromohymenialdisine (DBH)

 

Debromohymenialdisine (DBH) is an alkaloid originally isolated from the shallow-water Palauan marine sponge Stylotella aurantium. The molecule is intriguing not just for its drug-like properties, but also because it's simple molecular structure has yielded to easy total synthesis in the laboratory. Research suggest the compound acts as a highly selective inhibitor of a specific target cell DNA damage checkpoint enzyme during the G2 phase of the cell cycle. The compound is a promising potential Anti-Alzheimer agent.

 

Discodermolide

 

Discodermolide, isolated from the Bahamian deep-sea sponge Discodermia dissoluta, is a promising marine-derived candidate for treating certain cancers. It was discovered in 1987. The drug, a macrolide (polyhydroxylated lactone), is a member of a structurally diverse class of compounds called polyketides. It has a noteworthy chemical mechanism of action. It stabilizes the microtubules of target cells, essentially arresting them at a specific stage in the cell cycle and halting cell division. In addition to anticancer properties, discodermolide possesses immunosuppresive and cytotoxic activity. The pharmaceutical company Novartis Pharma AG licensed discodermolide for commercial development in 1998. The drug is currently in Phase I human clinical trials and continues to show promise in combating pancreatic cancer and many other drug-resistant cancers. Recently published reports offer up the exciting finding that combination drug treatment using discodermolide and Taxolå in lung cancer patients exhibits several times the tumor fighting efficacy of either drug administered on its own. 

 

Girolline (Girodazole)

 

Girolline was reported to inhibit protein synthesis in eukaryotic target cells. The compound was of interest because it inhibited protein synthesis at the termination steps of the process rather than at the initiation or chain elongation steps. The simple structure of the compound facilitated the production of a modified synthetic analog.

 

Halichondrins

 

A compound given the name halichondrin B, belonging to a chemical family known as the macrolides, was isolated by Uemura et al. (1985) from the Japanese sponge Halichondria okadai. Initial investigations into the bioactivity of the compound revealed that halichondrin B apparently bound tubilin at a site close to the so-called vinca site and altered tubulin depolymerization.

 

Hemiasterlins (H-286)

 

This class of novel marine oligopeptides have been shown to be potent antitumor agents. Representatives of this class of natural products have been isolated from extracts prepared from sponges residing in two distinct genera (Auletta; Siphonochalina). Three different hemiasterlins with drug development potential (hemiasterlin, hemiasterlin A, hemiasterlin C) have been the subject of chemical and biological investigations. These molecules exhibit cytotoxic and antitubulin activity similar to that seen in the dolastatins. Mitotic inhibition occurs through binding to tubulin at the vinca/peptide region in a manner similar to dolastatin. 

 

KRN7000

 

It was first isolated from the sponge Agelas mauritianus. These compounds, dubbed the agelasphins, were shown to exhibit antitumor and possible immunostimulatory activity.

 

Lasonolides

 

The lasonolides are a series of marine natural products under investigation for the treatment of cancer. The compounds were isolated in 1994 by scientists from the Harbor Branch Division of Biomedical Marine Research from the sponge Forcepia sp. found in Gulf of Mexico deep-sea habitats. These compounds are very potent and show especially promising properties for the treatment of pancreatic cancer. They kill cancer cells in a different way than most other cancer drugs. The exact mode of action is not yet fully understood, and is an area of active research. In addition to anti-proliferative and antitumor properties, these novel macrolide compounds display antifungal activity as well.

 

Manoalide

 

Manoalide was isolated from the sponge Luffariella variabilis collected in the Indo-Pacific. It is a member of a chemical family known as the sesquiterpenes. 
Although this natural product was originally reported as an antibiotic, follow-up work revealed manoalide possesses promising analgesic and anti-inflammatory properties. The compound works by inhibiting Phospholipase A2 (PLA2), which plays an important role in the inflammation process.

 

Topsentins

 

The Topsentins are a class of natural products that have been extracted from several sponge species subsequent to their initial isolation from the sponge Spongosorites ruetzleri. These compounds have been shown to have significant anti-inflammatory properties. Although the precise mode of action is not known, the compound has been reported capable of suppressing immunogenic as well as neurogenic (originating in nerve tissue) inflammation. The topsentins may hold promise as an arthritis medication or as additives in anti-inflammatory creams for the treatment of skin irritations.

 

Dictyostatin

 

Dictyostatin was first isolated in 1994 by Bob Pettit and his colleagues at Arizona State University from a sample of an unidntified dictyoceratid sponge of genus Spongiacollected in Jamaica. The compound was later isolated from from a lithistid sponge of the family Corallistidae and has been more fully repurified and characterized by researchers at Harbor Branch Oceanographic Institution and elsewhere. Dictyostatin inhibits the growth of human cancer cells and has been shown active against certain Taxol-resistant tumors. Its mechanism of action appears to be prevention of the breakdown of tubulin during mitosis in a fashion similar to the successful cancer drug Taxol. 

 

Laulimalide

 

Sometimes referred to as the fijianolides, the natural products laulimide and (the significantly less bioactive) isolaulimide were first extracted from the Pacific sponge Cacospongia mycofijiensis. The bioactivity displayed by these compounds is as microtubule stabilizing agents potentially arresting the development of target cells.

 

Peloruside A

 

University of Victoria scientist Peter Northcote and colleagues recovered the compound Peloruside A from the sponge Mycale hentscheli collected from Pelorus Sound, New Zealand. Peloruside A appears to bind tubulin and arrests target cell development at the G2-M transition stage of the cell cycle, triggering apoptosis ('cell suicide') before mitosis (M Phase) can begin. 

 

Salicylihalamides

 

The Vo-ATPases are a group of eukaryotic enzymes whose principal role is to pump hydrogen ions across cell vacuolar membranes. Salicylihalamides A and B, isolated from the sponge Haliclona sp. collected off of Westaen Australia, displays Vo-ATPase inhibitory activity that may eventually be incorporated into a drug designed to target these cell components. In addition to having potential as anti-tumor compounds, Vo-ATPases like the salicylihalamides may be capable of mediating the process of bone resorption. In this capacity, the compounds might form the basis for treatment of osteoporosis and similar diseases.

 

Cnidarian Derived Compounds

 

Pseudopterosins

 

The pseudopterosins were isolated from a Caribbean soft coral species called a sea whip (Pseudopterogorgia elisabethae). They belong to a class of compounds known as tricyclic diterpene glycosides. Pseudopterosins have been shown to possess potent anti-inflammatory and analgesic (pain relief) properties. They appear to work by inhibiting the synthesis of eicosanoids, (locally functioning hormone-like substances) in specific white blood cells called polymorphonuclear leukocytes.

 

Eleutherobin

 

Eleutherobin was first found in extracts made from the octocoral Eleutherobia sp. collected in Australia. The reported bioactivity of this natural product, currently under preclinical investigation, is as a microtubule binding agent similar to the anti-cancer drug taxol.

 

Sarcodictyins

 

Sarcodictyins were isolated from two Mediterranean coral species,Sarcodictyon roseum and Eleutherobia aurea. It acts as tubulin interactive agents.

 

Ascidian Derived Compounds

 

Aplidine (Aplidin¨)

 

Aplidine (Dehydrodidemnin B), has was isolated from the Mediterranean tunicate Aplidium albicans. It was first reported in a 1991 patent application. In preclinical animal tests, Aplidine exhibited anticancer properties. Aplidine differs chemically from didemnin B and the other didemnins only in the structure of its side chain. This fact, along with the small size and relatively simple structure, has allowed research to achieve total synthesis of didemnin analogs. The molecule has been described as a multifactorial apoptosis inducer, and it has other beneficial attributes such as low toxicity and a high specificity for tumor cells. The compound also inhibits the expression of receptor proteins (ornithine descarboxylase) and the secretion of proteins (vascular endothelial growth factor) involved in growth and vascularization of certain tumor types. 

 

Didemnin B

 

Didemnin B was originally isolated from the Caribbean tunicate Trididemnum solidum and first reported in the literature in 1981. Early investigation into the bioactivity of this compound revealed marked antiviral and cytotoxic activity in in vitro tests using standard mouse leukemia cell lines. Mechanistically, Didemnin B interrupts protein synthesis in target cells by binding non-competitively to palmitoyl protein thioesterase. Didemnin B was the first defined marine natural product to enter clinical trials as a potential anti-cancer drug.

 

Ecteinascidin 743 (Yondelis¨)

 

Ecteinascidin 743 was isolated from the Caribbean sea squirt (Ascidia) Ecteinascidia turbinate. It is classified as a tetrahydroisoquinoline alkaloid. Preclinical trials showed ET-743 was active against a range of tumor types in standard animal models. Subsequent human trials showed efficacy against advanced soft tissue sarcoma, osteosarcoma and metastatic breast cancers. Research into the mode of action of ET-743 has revealed that binding of the drug to target cell DNA inhibits cell division and leads to apoptosis of cancer cells. ET-743 has been co-developed under the trade name Yondelis¨ by the Spanish marine pharmaceutical company PharmaMar and Johnson & Johnson subsidiary Ortho Biotech.

 

Diazonamide A

 

The marine natural product Diazonamide A was first reported in 1991. It was extracted from the Philippine ascidian Diazona angulata by the William Fenical Chemistry Lab at the Scripp's Institution of Oceanography. Both analogs possess potent microtubulin interactive activity. Diazonamide A is an inhibitor of microtubule assembly, arresting the process of cell division in cultures exposed to treatment. Examination of treated cells reveals a loss of spindle microtubule assemblies and also microtubules associated with the interphase stage of the cell cycle. 

 

Vitilevuamide

 

Vitilevuamide is a bioactive cyclic peptide has been isolated from the ascidians Didemnum cuculiferum and Polysyncraton lithostrotum (the same animal is the source of the antimicrobial/antitumor compound namenamicin). Vitilevuamide is one of several novel tubulin interactive agents recently discovered from marine invertebrate sources. Research on the mechanism of action of this two-ringed marine peptide reveal that vitilevuamide inhibit tubulin polymerization and can arrest the cell cycle of target cells in the G2/M phase.

 

Bryozoans Derived Compounds

 

Bryostatin 1

 

This natural product was originally extracted from the bryozoan (a sessile, moss-like marine animal) Bugula neritina collected in the Gulf of California and Gulf of Mexico. More recent work has demonstrated that the compound is most likely produced by the microbial symbiont Endobugula sertula. This compound and other bryostatins produced by the microbial associate are exploited by the host as a chemical means of defense, particularly in the larval stage. Bryostatin 1 is a macrocyclic lactone that belongs to a diverse class of complex products called polyketides. The compound has demonstrated promising anti-cancer, anti-tumor, and immunostimulant activities that are apparently related to its ability to bind to protein kinase C, and enzyme involved in the up-regulating (switching on) and down-regulating (switching off) of certain proteins. 

 

Helminth Derived Compounds

 

Anabaseine (Hoplonemertine toxin)

 

Anabaseine is a nicotinoid alkaloid. It is capable of stimulating vertebrate neuromuscular nicotinic receptors and increasing cholinergenic transmission. As such it has potential as a treatment of cognitive function loss. A synthetic analog, DMXBA (GTS-21) has exhibited memory enhancing effects in recipients. The compound is currently under license by the Japanese pharmaceutical company Taiho and is in Phase I trials for treating Alzheimer's disease.

 

Microbe Derived Compounds

 

Cryptophycins

 

This family of compounds was initially reported from a terrestrial source (the Nostoc sp. cyanophyte component of a Scottish lichen). Representative compounds have also been found in species of free-living marine and non-marine cyanophytes and, more recently, from the Japanese sponge Dysidea arenaria. The expressed bioactivity that was originally pursued was activity as an antifungal agent. Development of the compound for this purpose was not pursued beyond preliminary investigations when it was deemed too toxic for human use. More recently it has been reported that cryptophycin 1 is an inhibitor of tubulin assembly in cells.

 

Curacin A

 

First isolated from Lyngbya majuscula by Gerwick et al. and reported in 1994, this natural product appeared to be a very potent tubulin interactive compound. It proved to be highly insoluble, however, so much so that bioactivity could not be demonstrated with in vivo animal models.These compounds are currently undergoing preclinical evaluation as potential future drugs.

 

Thiocoraline

 

Belonging to the chemical family known as the thiodepsipeptides, thiocoraline was first isolated from Micromonospora marina, an actinomycete bacterium collected from coastal Mozambique, southeast Africa. The Spanish marine drug company PharmaMar has reported that the compound shows activity against several standard drug screens, including breast cancer, colon cancer, renal cancer, and melanoma. Target cells appear to be inhibited through inhibition of DNA polymerase ± enzyme.The most recent published literature suggests thiocoraline is still undergoing advanced preclinical evaluation.

 

The Future Of Marine Bioprospecting

 

In the near future, marine bioprospecting efforts will likely focus not only on natural products from ocean plants, animals, and microbes, but also on the potential for biotech to exploit the information stored in the genomes of these organisms. In the wake of the Human Genome Project and with the expertise and technology that emerged from it, scientists are sequencing increasing numbers non-human genomes. Total genome sequencing of a handful of marine microbes has been completed, and the first sequencing of marine vertebrate (e.g., fish) genomes has commenced as well. This and similar research will likely lead to the development of gene probes that can identify the genes in target organisms that code for the elaboration of novel natural products of potential value to humans. Increasingly, new projects are expected to target the as yet unrealized biomolecular potential of the vast and almost entirely unknown marine microbial community. These research efforts could be instrumental in developing the next generation of pharmaceuticals for improving human health, as well as contributing to improved animal and agricultural crop health.

In summary, the marine world has become an important source of therapeutic agents with novel mechanisms of action. Even though thousands of new molecules are discovered every year only small number of candidates is incorporated in clinical trials. The main problem underlying this is sustainable supply of these compounds from natural sources. To battle this problem various strategies are developed, such as mariculture or aquaculture of source organisms, development of synthetic analogues of active compounds, fermentation of microorganisms producing the compound, etc. Another possible solution is the use of genetic engineering to transfer the genes encoding the synthetic enzymes that produce the desired compound to microorganisms that can be grown in huge quantities. Development of these products and services, as well as the fundamental research from which they must be derived will be enhanced by greater dependence on interdisciplinary sciences such as pharmacology, chemical ecology, molecular biology, genomics, metagenomics, computational and combinatorial chemistry and biology.

The field of marine natural products is passing its discovery phase and moving to the second phase where understanding relationships and processes is driving the research towards novel drugs from the sea. Marine plants, animals and microorganisms will be the basis of new products and services important to technology in the future. With rich biodiversity and vast marine resources along the Indian coast, in the form of estuaries, creeks, deep seas and continental shelf, the opportunities for research in the area of marine drug development are endless.

 

References

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