Article

Marine natural products in drug discovery Narsinh L Thakur1*, Archana N Thakur2, and Werner E G Müller3 1

Nicholas Piramel Research Centre, 1, Nirlon Complex off Western Express Highway, Goregaon(East), Mumbai-400 063, India 2 Department of Zoology, D. G. Ruparel College, Mahim, Mumbai-400 016, India 3 Institute for Physiological Chemistry, Department of Molecular Biology, University of Mainz, Duesbergweg 6, D-55099 Mainz, Germany *Corresponding author, E-mail: [email protected] Received 3 February 2005; Revised 14 March 2005

Abstract Marine organisms comprise approximately a half of the total biodiversity, thus offering a vast source to discover useful therapeutics. In recent years, a significant number of novel metabolites with potent pharmacological properties have been discovered from the marine organisms. Although, there are only few marine derived products currently in the market, several marine natural products are now in clinical trials. Current research activities, while primarily within the academic laboratories, have generated convincing evidence that marine natural products have an exceedingly bright future in the discovery of life saving drugs. Keywords: Marine natural products, Marine organisms, Microorganisms, Novel metabolites, Drugs. IPC code; Int. cl.7 ⎯ A61K 35/00, A61K 35/66, A61P, A61P 35/00

Introduction Oceans cover nearly 70% of earth’s surface and possesses nearly three lakh described species of plants and animals from marine sources, representing 34 - 36 Phyla and some of them are exclusively of the marine ecosystem (Argulis & Schwartz, 1982; Pomponi, 1999; Jimeno, 2004; Kijjoa & Swangwong, 2004). It is reported that the first living organisms were appeared in the sea more than 3500 million years ago (Macdougall, 1996; Argulis & Schwartz, 1982) and evolutionary development has equipped many marine organisms with the appropriate mechanisms to survive in a hostile milieu in terms of extreme temperatures, changes in salinity and pressure as well as overcoming the effects of mutation, bacteria and viral pathogens (Jimeno et al, 2004). The diversity in species is extra-ordinarily rich on coral Vol 4(6) November-December 2005

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reefs, where there are around 1000 species per square meter in some areas and the Indo-Pacific Ocean has the world’s greatest tropical marine biodiversity (Pomponi, 1999). Marine organisms have developed exquisitely complex biological mechanisms showing cross phylum activity with terrestrial biota. In terms of evolution and biodiversity, the sea appears to be superior to the terrestrial ecosystem; marine species comprise approximately

Sponges produce

Sponge Suberites domuncula

Ascidian Didemnum psamathodes

a half of the total biodiversity, thus offering a vast source to discover useful therapeutics. Humans have been attempting to understand and use oceanic resources since ancient times. Ancient maritime people, notably the Chinese and Japanese, ate a variety of iodinerich seaweeds that undoubtedly accounted for their low incidence of goiter. Chinese Pharmacopoeia recommends cytotoxic compounds, possible use in cancer treatment recipes for a number 471

Article of disorders such as pain, menstrual difficulties, abscesses and cancer (Ruggieri, 1976). Coral Reef products have also been traditionally used for treating various ailments in Taiwan, Japan, China and India. Historical records show that human being has become aware of the venomous nature of some sea creatures for at least 4000 years (Colwell, 2002). It has been known for centuries that sponges contain bioactive compounds that are of potential medical importance. Richter in 1907 outlined that the active component of the roasted bath sponge, used already by Roger against struma, is iodine. In the 19th and early 20th centuries, cod liver oil was in use as supplementary nourishment. However, only in middle of 20th century scientists began to systematically probe oceans for medicines. By the early 1950s, Ross Nigrelli of the Osborn Laboratories of the New York aquarium (New York Zoological Society), extracted a toxin from cuvierian organs of the Bahamian sea cucumber, Actynopyga agassizi. He named this toxin as ‘Holothurin’, which showed some antitumour activity in mice (Nigreli et al, 1967). Although, ‘Holothurin’ was never commercialized, the search for drugs from the sea has continued.

Marine chemical ecology Several marine organisms are sessile and soft bodied, then the question will arise; how do these delicate looking simple sea creatures protect themselves from predators and pathogens in the marine environment? While answering this interesting ecological question, researchers found that marine organisms 472

have defensive chemical weapons (secondary metabolites) for their protection. Intensive evolutionary pressure from competitors, that threaten by overgrowth, poisoning, infection or predation have armed these organisms with an arsenal of potent chemical defense agents. They have evolved the ability to synthesize these chemical weapons or to obtain them from marine microorganisms. These compounds help them to deter predators, keep competitors at bay or paralyze their prey. Investigations in their chemical ecology have revealed that the secondary metabolites not only play various roles in the metabolism of the producer but also in their strategies in the given environment. The diversity of secondary metabolites produced by marine organisms has been highlighted in several reviews (Munro et al, 1999; Faulkner, 2002; Proksch et al, 2002; Haefner, 2003; Jimeno et al, 2004; Jha & Zi-rong, 2004). They range from derivatives of amino acids and nucleosides to macrolides, porphyrins, terpenoids to aliphatic cyclic peroxides and sterols. There is ample evidence documenting the role of these metabolites in chemical defense against predators (Schupp et al, 1999; Pisut & Pawlik, 2002) and epibionts (Wahl et al, 1994; Thakur & Anil, 2000; Thakur, 2001; Thakur et al, 2003). The studies on marine chemical ecology include three different aspects. Firstly, diversity of chemical compounds produced by different organisms; secondly, potential functions of these metabolites in nature and finally, the strategies for their use for human benefit (Müller et al, 2003).

Marine chemical warfare and human health To understand the link between marine chemical warfare and human health it is crucial to study chemical ecology in the oceans. Many sessile invertebrates such as sponges, corals and tunicates feed by filtering seawater. Since, seawater contains high concentrations of bacteria, these organisms produce antibiotics to defend themselves from potentially harmful microorganisms. Thus, the production of anti-bacterial compounds by filter feeders such as sponges provides a possible link between chemical defense for sponges and antibiotics for use in humans. However, why should a sponge produce anticancer drugs or why should a coral produce a compound useful in the treatment of arthritis? In the scenario of two encrusting sponges growing together, the sponge that will win the race of competition for space is the one that produces the chemical most effective at killing the rapidly dividing cells of the neighboring sponge. The ability of chemical to kill rapidly dividing cells is the hallmark of chemotherapy. Anticancer drugs often act by killing the rapidly dividing cells of a tumour but generally do not harm ‘normal’ healthy cells. These ideas provide a connection between marine chemical warfare and the possible application of marine natural products in medicine. Chemical ecology of marine organisms relates very closely to biotechnology by exploring these secondary metabolites to develop drugs to treat various life threatening diseases. Natural products released into the water are rapidly diluted and therefore need to be highly potent to have any effect. For Natural Product Radiance

Article this reason, and because of the immense biological diversity in the sea as a whole, it is increasingly recognized that a huge number of natural products and novel chemical entities exist in the ocean with biological activities that may be useful in the quest of finding drugs with greater efficacy and specificity for the treatment of many human diseases (Mayer, 2000; Proksch et al, 2002).

stages, are discussed in this article (Table 1). Some of the commercialized products from marine organisms include antibiotic Cephalosporin from marine fungi, cytostatic Cytarabine from sponge, anthelmintic insecticide Kanic acid from red alga, analgesic Zincototide from mollusk, etc. Antiviral compound Ara-A (active against Herpes virus) and antitumour compound Ara-C (effective in acute lymphoid leukaemia) were obtained from the sponge and these compounds are Current status now in clinical use (Guyot, 2000). The number of potential Arabinosyl Cytosine (Ara-C) is currently compounds isolated from marine realm sold by the Pharmacia and Upjohn has virtually soared and this number now Company under the brand name Cytosarexceeds to 10,000, with hundreds of new UR. Some of the interesting marine compounds still being discovered every bioactive molecules are listed below with year (Proksch et al, 2002). With the their mechanism of action. combined efforts of marine natural product chemists and pharmacologists, a Ion channels targeting number of promising identified molecules molecules: are already in market, clinical trials or in Cone snail venoms are highly pre-clinical trials. Interestingly, these potent and act as selective peptide precious natural products have been obtained from marine antagonists and G protein coupled microorganisms as well as invertebrates receptors (GPCR) (Jones & Bulaj, 2000). such as sponges (Thakur & Müller, 2004), Some of the members of conotoxin family molluscs, bryozoans, ascidians, etc. such as ω-conotoxins are calcium channel Selected marine natural products, which blockers, κ-conotoxins are potassiumare in market and in different clinical

Sponges

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Sponge cell surrounded by bacterial colony

channel blockers and µO-conotoxins are sodium channel blockers. Pharmacologists are investigating the possible use of these potent toxins as adjuncts in anaesthesis, analgesics or the drugs for the treatment of epilepsy, cardiovascular disease and psychiatric disorders. The available conotoxin libraries are thought to contain more than 50,000 distinct molecules and the strong commercial interest in these molecules is reflected by more than 100 patents and patent applications with the word ‘conotoxin(s)’ in their title. Compounds targeting enzymes ⎯ Enzyme inhibitors have received increasing attention as useful tools in the study of enzyme structures and reaction mechanisms and also find applications in pharmacology and agriculture. Recently, marine organisms are increasingly recognized as a fruitful source for potential enzymes inhibitors (Haefner, 2003). For example a bryozoan, Bugula neritina, has been the source of a family of protein kinase C (PKC) inhibitors called bryostatins, which are currently in clinical trials for cancer (Haefner, 2003). Bryostatin-1 has been granted Orphan Drug status and has been designated an Orphan Medicinal Product in Europe for esophageal cancer in combination with Paclitaxel (Clamp & Jayson, 2002). In humans, Phospholipase A2 (PLA2) is involved in the pathogenesis of variety of inflammatory diseases. PLA2 is therefore seen as a promising target for the development of anti-inflammatory drugs. The first natural marine human synovial PLA2 inhibitor, the sester terpene manolaide, was isolated from the Palauan sponge, Luffariella variabilis and was 473

Article found to have analgesic and antiinflammatory activity (Soriente et al, 1999). There after several PLA2 inhibitors were isolated from marine sources. DNA-interactive agents ⎯ Several established anticancer drugs are DNA-interactive agents. However, due to lack of specificity of these drugs for cancer versus normal cells, the question of whether DNA can be a suitable target to develop anticancer drugs has been raised. Support for the idea that DNA is still a target worth aiming at has come from the clinical trials with a marine natural product, ET743 (YondelisTM). ET743, with broad spectrum anti-tumour activity was originally identified in 1988 by Kenneth Rinehart’s team at the University of Illinois, Urbana-Champaign (Rinehart 2000) and licensed to PharmaMar in 1994. Other

the separation of chromosomes in the final M Phase of the cell cycle. With the success story of tubulin-binding agent like Taxol, research in this area has been prompted to explore microtubule targeting agents from different sources including marine organisms (Haefner, 2003). Several compounds have been yielded from marine sources, which includes, Discodermolide (sponge), Eleutherobin (soft coral), Dolastatin (sea hare), Dictyostatin-1 (sponge; Isbrucker et al, 2003), Halichondrin B (sponge), etc. All of these compounds have been reported to exhibit general cytotoxicity, but only Dolastatin 10, the Dolastatin 15 analogues ILX651, Cemadotin, Discodermolide and Hemiasterlin analogue HTI286 have so far reached clinical development (Haefner, 2003). Other marine natural Table 1 : Selected example of marine natural products, products ⎯ Other marine natural which are currently in market or in clinical phases products in clinical trials include AplidinTM, a cyclic depsipeptide derived Product Source Application area Status from sea squirt, which triggers rapid and persistent activation of the apoptotic Ara-A Marine sponge Antiviral Market process as a consequence of the induction Ara-C Marine sponge Anticancer Market of oxidative stress (Cuadrado et al, Cephalosporins Marine fungi Antibiotic Market Conotoxins Cone snail Chronic pain Phase I/II/III 2003). Sequalamine lactate, a novel antiangiogenic aminosteroid from the GTS21 Nemertine worm Alzeimer’s disease Phase I/II dogfish shark, Squalus acanthias is LAF389 Sponge Cancer Phase I currently in clinical phase II for Bryostatin-1 Bryozoan Cancer Phase II Yondelis™ Sea squirt Cancer Phase II/III ovarian and non-small cell lung cancer (Cho & Kim, 2002). IPL512602, a Dolastatin-10 Sea slug Cancer Phase II synthetic analogue of the steroid ILX651 Sea slug Cancer Phase I Contignasterol isolated from the sponge, Cemadotin Sea slug Cancer Phase II Petrosia contignata (Burgoyne & Discodermolide Sponge Cancer Phase I Anderson, 1992) is in phase II clinical HTI286 Sponge Cancer Phase I trials as a leukocyte-suppressing antiAplidinTM Sea squirt Cancer Phase II inflammatory drug for the treatment of Squalamine lactate Shark Cancer Phase II asthma. IPL512602(steroid) Sponge Inflammation, Asthma Phase II Apart from these, fish oils are source of polyunsaturated fatty acids (Reference: Haefner, 2003)

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DNA-interactive agents from marine sources include Dercitin, an acridine alkaloid isolated from a sponge of the genus Dercitus and the Topsentins, a class of sponge-derived bisindole alkaloids (Burres et al, 1991), but ET743 is so far the only compound that has gone into clinical development. Microtubule-interfering agents ⎯ Since cancer is the result of uncontrolled cell division, it has long been recognized in the field of medical research that microtubule-interfering agents could prove valuable for cancer chemotherapy. The microtubule inhibitors act at the G2 and M phases and lack some of the worst effects of medicines that block DNA synthesis. They do not act on DNA directly, but prevent the formation of the internal microtubules that play a role in

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Article (PUFA) and are also of interest due to their physiological effects like prevention of atherosclerosis, their role in anti-ageing and in brain development in premature infants.

Marine microorganisms in drug discovery Marine microbes having immense genetic and biochemical diversity look likely to become a rich source of novel effective drugs. Marine bacteria constitute ~10% of the living biomass carbon of the biosphere (Parkes et al, 1994) and they represent dramatically different environment than their terrestrial counterpart. These bacteria originate mainly in sediments but also occur in open oceans and associated with the marine organisms. It was surprising to find that many bioactive compounds, reported from marine invertebrates are produced by their microbial symbionts. Competition among microbes for space and nutrients in the marine environment is a driving force behind the production of such precious antibiotics and other useful pharmaceuticals. Interestingly, microorganisms associated with marine invertebrates are proved to be valuable candidates for drug discovery program (Jensen & Fenical, 2000; Hentschel et al, 2003; Imada, 2004; Thakur et al, 2005). Actinomycetes are an important group of bacteria, producing over 70% of naturally occurring antibiotics as well as other bioactive compounds. As the oceans are also a titanic reservoir of novel actinomycete taxa, the efforts are underway to search antibiotics from this source. Prof. Jensen and Prof. Fenical of Vol 4(6) November-December 2005

AquaPharm Biodiscovery Ltd. (UK) is a marine biotechnology company, dedicated to the discovery and commercialization of novel nutraceutical and pharmaceutical products. Nereus Pharmaceutical (USA) also has strong R&D program in the field of marine natural products and they have several molecules in clinical trials. The lead molecules in Nereus' pipeline have come from its marine microbial discovery platform, which the Company expects will be the next significant source of drug discovery for new pharmaceutical agents. Other pharmaceutical companies like Aventis, Neurex, Novartis and Wyeth are also working in the field of marine natural products. India is blessed with a more than 8000 km of coastline, possessing over 2 million sq. km. exclusive economic zone (EEZ). Indian coastline has every type of marine habitats like inter-tidal rocky, muddy and sandy shores, coral reefs and mangrove forests. However, the potential of this domain as the basis for new biotechnologies remains largely unexplored. Some of the selected institutes like NIO, Goa; CDRI, Lucknow; Bose Institute, Kolkata; CIFE, Mumbai; RRL, Bhubaneswar; Annamalai University and Mumbai University are engaged in the exploration of life saving drugs from Pharmaceutical research marine sources and many other Indian Institutes, Universities and Pharmaceutical Pharmaceutical industry now companies have also recognized the accepts the world’s oceans as a major significance of this subject. International frontier for medical research. PharmaMAR research institutes acknowledged the (Spain & USA): has taken leading position importance of establishing interdisciplinary in the development of drugs from the sea. research centers focusing on marine They have four novel compounds, natural products. Similar efforts should YondelisTM, Aplidin®, Kahalalide F and be made in India in order to explore ES-285 in clinical trials and have a rich biotechnological potential of India’s pipeline of preclinical candidates. untapped marine biodiversity. Scripps Institute of Oceanography, USA, recently reviewed the status of numerous potential drugs, isolated from marine microorganisms (Jensen & Fenical, 2000). Like bacteria, marine fungi are also reported to be a potential source of bioactive substances (Proksch et al, 2002). Sorbicilactone-A, noveltype alkaloid was reported from sponge (Ircinia fasciculata) associated fungus, Penicillium chrysogenum. This compound showed promising activities in several mammalian and viral systems and qualified for therapeutic human trials (Bringmann et al, 2003). Polyketide synthases (PKSs) are a class of enzymes that are involved in the biosynthesis of secondary metabolites such as Erythromycin, Rapamycin, Tetracycline, Lovastatin and Resveratrol (Saxena et al, 2003). Polyketide biosynthetic genes from bacteria and fungi have been cloned, sequenced and expressed in heterologous hosts. Some marine sponge associated bacteria with antimicrobial assets are also detected to have polyketide synthases gene clusters and investigation is underway to explore them. Deep-sea hydrothermal vent microorganisms are also reported to produce unusual bioactive metabolites.

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Article Conclusion As described in this article, the rich diversity of marine biota with its unique physiological adaptations to the harsh marine environment provides a fruitful source for the discovery of life saving drugs. With the implementation of scuba diving tools and the development of the sophisticated instruments for the isolation and elucidation of structures of natural products from marine organisms, a new and exciting vista is open for the exploration of precious drugs. However, it must be acknowledged that supply problems still hamper the development of many promising metabolites of marine origin and have stimulated research on alternative methods for marine metabolite production. Isolation and cultivation of suspected microbial producers of bioactive natural products could provide much needed answer to the supply problem. By using molecular biological approach, it is also under investigation to transfer a bacterial gene cluster, responsible for the biosynthesis of desired natural product to a vector suitable for large-scale fermentation. In summary, world’s oceans could play an important role in supplying life saving drugs in future. Although substantial progress has been made in identifying novel drugs from the marine sources, great endeavors are still needed to explore these molecules for clinical applications.

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Producing drugs from marine sponges Marine sponges are potential sources of many unique metabolites, including cytotoxic and anticancer compounds. Natural sponge populations are insufficient or inaccessible for producing commercial quantities of metabolites of interest. Sponges can be cultivated from cuttings taken from a parent and ‘planted’ in the sea or the better-controlled environments of aquariums. In addition, culture of sponge cells and various types of cell aggregates provides an alternative method for producing sponge metabolites. A review published by a team of scientists at Spain and New Zealand focuses on methods of producing sponge biomass to overcome Vol 4(6) November-December 2005

supply limitations. Production techniques discussed include aquaculture in the sea, the controlled environments of aquariums, and culture of sponge cells and primmorphs. Cultivation in the sea and aquariums are currently the only practicable and relatively inexpensive methods of producing significant quantities of sponge biomass. In the future, metabolite production from cultured sponge cells and primmorphs may become feasible however, cell and primmorph cultures are not feasible at present for producing large amounts of biomass. The authors summarized that the major questions remain concerning the

production of sponge-sourced bioactives: can methods be developed for culturing healthy sponge without its endosymbionts? Can endosymbiotic bacteria be cultured in the absence of live sponge tissue and cells, to produce metabolites of interest? Studies are needed of sponge nutrition and how nutrition can influence growth and metabolite production. What might be the influence of precursor feeding? All these and many other questions remain to be answered [Belarbi El Hassan, Gómez Antonio Contreras, Chisti Yusuf, Camacho Francisco García and Grima Emilio Molina, Producing drugs from marine sponges, Biotechnol Adv, 2003, 21 (7), 585-598].

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