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| REVIEW ARTICLE |
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| Year : 2016 | Volume
: 8
| Issue : 2 | Page : 83-91 |
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Exploring the ocean for new drug developments: Marine pharmacology
Harshad Malve
Lead Medical, Asia Pacific Region, Ferring Pharmaceuticals Pvt. Ltd., Elphinstone (West), Mumbai, India
| Date of Submission | 05-Jun-2015 |
| Date of Decision | 11-Jul-2015 |
| Date of Acceptance | 25-Jul-2015 |
| Date of Web Publication | 28-Mar-2016 |
Correspondence Address:
Harshad Malve
Lead Medical, Asia Pacific Region, Ferring Pharmaceuticals Pvt. Ltd., Elphinstone (West), Mumbai
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0975-7406.171700
 Abstract | | |
Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the existing resources for the drugs. And hence, the drug manufacturers are always on the lookout for new resources to develop effective and safe drugs for the increasing demands of the world population. Seventy-five percentage of earth's surface is covered by water but research into the pharmacology of marine organisms is limited, and most of it still remains unexplored. Marine environment represents countless and diverse resource for new drugs to combat major diseases such as cancer or malaria. It also offers an ecological resource comprising a variety of aquatic plants and animals. These aquatic organisms are screened for antibacterial, immunomodulator, anti-fungal, anti-inflammatory, anticancer, antimicrobial, neuroprotective, analgesic, and antimalarial properties. They are used for new drug developments extensively across the world. Marine pharmacology offers the scope for research on these drugs of marine origin. Few institutes in India offer such opportunities which can help us in the quest for new drugs. This is an extensive review of the drugs developed and the potential new drug candidates from marine origin along with the opportunities for research on marine derived products. It also gives the information about the institutes in India which offer marine pharmacology related courses. Keywords: Anticancer, bryostatin, cytarabine, keyhole limpet hemocyanin, mariculture, sponge, ziconotide
How to cite this article:
Malve H. Exploring the ocean for new drug developments: Marine pharmacology. J Pharm Bioall Sci 2016;8:83-91 |
Ocean represents a source of a varied type of organisms due to the diversified environment offered by different oceanic zones. The enormous ecological resources of the sea have been exploited since ancient times and included the use of marine animals like fish and preparations from algae as the sources of medicine. Fish oils are the classic example of marine-derived product in use since ages. Marine pharmacology is a branch of pharmaceutical sciences which focuses on the substances with active pharmacological properties present in marine species of plants and animals. Marine environment is an exceptional store house of novel bioactive natural products, with structural and chemical features generally not found in terrestrial natural products. The marine organisms also provide a rich source of nutraceuticals and potential candidates for the treatment of several human diseases. The modern day focus of marine pharmacology is on microbes.[1] This includes the discovery of new pharmaceutical candidates from marine microbes.[2] The ocean provides enormous opportunities to discover new compounds as it has more than 13,000 molecules described out of which 3000 are having active properties.[3] Marine natural products are generally secondary metabolites. They are not generated by biological or regular metabolic pathways and have no primary function associated with the development, growth, or propagation of a species.[4] Sixty-three percentage of the new drugs are classified as naturally derived (i.e., modified natural product, unmodified natural product or synthetic compound with a natural product as pharmacophore). Covering the period from 1981 to 2008, around 68% of all the drugs used to curb infection (including antibacterial, antiviral, antiparasitic, and antifungal compounds) and 63% of anti-cancer drugs were naturally derived.[5]
| Biodiversity of Marine Environment | |  |
Marine environment is a natural habitat for a broad variety of living organisms having different physiology and capacity to adapt their environment. Out of over 33 animal phyla known today, a total of 32 phyla are embodied in the marine environment out of which 15 varieties are exclusively present in the marine environment.[6] Such genetic diversity renders chemical diversity which is promising for new drug development.
Oceans contain more than 80% of diverse plant and animal species in the world. Marine organisms such as sponges, tunicates, fishes, soft corals, nudibranchs, sea hares, opisthobranch Molluscs, echinoderms, bryozoans, prawns, shells, sea slugs, and marine microorganisms are sources of bioactive compounds (viz. oils and cosmetics).[7] The first biologically active marine natural product was formally reported in late 1950 by Bergmann.[8] In late 1970, it was established that marine plants and animals are genetically and biochemically unique. Around 15,000 such unique natural compounds have been described and out of them 30% products have been isolated from sponges.[9] The remarkable discovery of unusual arabino-or ribo-pentosyl nucleosides in marine sponges was the first illustration that is naturally occurring nucleosides could contain sugars other than ribose and deoxyribose.[10] It was also observed that molecules of marine origin can be accepted by humans with minimal manipulation.[3]
There are some reports on the characterization of the antimicrobial activity of marine macroorganisms collected from the Indian coastline have appeared. Streptomyces sp. has been the most widely studied microbial species from the Indian coastal waters as a source of antibiotics.[11] In a study, 75 bacterial strains from 4 species of marine sponges were isolated, out of which 21% of the isolates have shown good antibacterial activity, with some of the strains showing species specificity.[11] The study indicated the diversity of antibiotic producing marine bacteria and also established that sponges are a rich source of bacteria capable of producing novel pharmacologically active molecules.
| Marine Pharmacology in India | | |
India has over 8000 km of coastline with clusters of marine habitats like inter-tidal rocky, muddy and sandy shores, coral reefs, and mangrove forests. The potential of Indian marine habitat has remained largely unexplored for their potential of new drugs and biotechnological programs. Some of the selected institutes such as National Institute of Oceanology, Goa; Central Drug Research Institute, Lucknow; Bose Institute, Kolkata; Central Institute of Fisheries Education, Mumbai; Regional Research Laboratory, Bhubaneswar of Council for Scientific and Industrial Research are presently working for exploration of life saving drugs from marine sources. Many other Indian institutes, universities, and pharmaceutical companies have also recognized the significance of this subject.[12]
Marine pharmacology has been reviewed extensively in the past all over the world as well as in India, but still there is a need to review the potential of the oceans as source for the development of new drugs, considering the advantage of their abundance in nature and large scale production. At present, the drug industry is working on screening and isolation of novel molecules with unreported pharmacological properties that can be exploited for the development of new therapeutic agents for commercial use. This review has largely focused on different classes of marine drugs currently in use and at different stages of trials for approval and marketing in future. The review has also tried to delve into the limitations and future trends of the drugs from marine sources.
| Classification of Marine Pharmacology | | |
Marine pharmacology can be classified on the basis of source of the candidate drug[9]
- Genetically engineered marine organisms
- Manufacture of pharmaceuticals and nutraceuticals of marine origin
- Chemicals produced by or found in marine organisms shown to have a wide variety of applications as pharmaceuticals.
Marine drugs can be broadly classified based on their actions as follows:
Antibacterial
Eicosapentaenoic acid, a polyunsaturated fatty acid, isolated from a diatom of marine origin Phaeodactylum tricornutum which has shown activity against an array of Gram-positive and Gram-negative bacteria, which also includes a multidrug-resistant variety of Staphylococcus aureus.[13]
Anti-inflammatory
The anti-inflammatory function of extracts and other parts of a Mediterranean sponge species Spongia officinalis in the in vivo study on rat model of carrageenan-induced paw edema assay.[14]
Neuroprotective
The extracts of South Indian green seaweed Ulva reticulata has shown neuroprotection by inhibiting acetyl-and butyryl-cholinesterases, efficacy comparable to agents currently approved for Alzheimer's disease treatment.[15]
Antiparasitic
Extracts of Sarcotragus sp. known as Tunisian sponge prepared in dichloromethane has demonstrated in-vitro anti-leishmanial activity by demonstrating the associated morphological alterations in promastigotes of leishmania major.[16]
Antiviral agents
Anti-herpes simplex virus-1 (HSV) activity found in high molecular weight exo-polysaccharides extracted from the Celtodoryx girardae (French marine sponge) and its associated symbiotic bacteria has been reported.[17]
Anticancer
Bryostatin, primarily obtained from the Bryozoan, Bugula neritina, although some forms have been extracted from sponges and tunicates. Sorbicillin-derived alkaloids sorbicillactone A and its 2', 3'-dihydro analog sorbicillactone-B has shown activity against leukemia cells free from any noteworthy cytotoxicity. Sorbicillactone-B has been derived from a salt-water culture of a bacterial strain Penicillium chrysogenum which has been isolated from a sponge Ircinia fasciculata, a Mediterranean sponge specimen.[18]
Another promising anticancer drug used as an immunotherapeutic agent is keyhole limpet hemocyanin (KLH). KLH is a copper containing extracellular respiratory protein present in Megathura crenulata, a marine Gastropod species found in large numbers at the Pacific coast of California and Mexico. KLH is found in two isoforms KLH1 and KLH2.[19] KLH is reported to possess remarkable immunostimulatory properties in experimental animals and human, used in experimental immunology and also clinically as an immunotherapeutic agent.[20] KLH is specifically used in clinical setup for the treatment of bladder carcinoma, and its efficacy is perhaps due to a cross-reacting carbohydrate epitope. KLH may also have significant potential for the treatment of other types of cancers, particularly the adenocarciomas derived from the epithelium, by using it as a carrier for gangliosides of carcinoma and mucin-like epitopes.[19]
KLH is intravesically administered to patients with bladder carcinoma. Its clinical success in carcinoma patients is attributed to the presence of the disaccharide epitope Gal (β1-3), Ga1NAc.[21] This epitope of KLH is believed to be cross-reactive with an equivalent epitope on the urinary bladder tumor cell surface. The cumulative cellular and humoral immunological responses to KLH can result in a cytolytic reduction of tumor growth.[19]
In addition to tumor immunotherapy, KLH is also prescribed in the following conditions:[19]
- As a generalized vaccine component for antigen presentation, alone or in adjuvant cocktail
- For diagnosis of schistosomiasis because of cross-reactivity to one of the epitopes on larval schistosomes
- In drug assays
- Treatment of drug addiction by immunoassay for abused drugs
- For immune competence testing
- Assessment of stress and inflammation.
Analgesic
Ziconotide was the first drug of marine origin to obtain approval from the U.S. Food and Drug Administration (USFDA) in 2004 to treat pain. It is also known as Prialt, and it was originally extracted from the marine snail Conus magus. Results from animal studies suggested the role of ziconotide in blocking of N-type calcium channels on the primary nociceptive nerves of the spinal cord.[22]
Antimicrobial
The cephalosporins are well-known antimicrobial agents with a marine source of origin. Cephalosporin C was firstly extracted and purified from a marine fungus, Cephalosporium acremonium.[9]
Antimalarial activity
Isonitrile containing antimalarial molecules have been extracted from the Acanthella sp., a Japanese sponge. The isolated molecules belong to kalihinane diterpenoids class, which also contains antifungal, anthelmintic, and antifouling compounds.[23]
| Evolution of Marine Pharmacology | | |
The recent global marine, pharmaceutical pipeline consists of only 3 USFDA approved drugs, and one European Union (EU) registered drug. Currently, marine drugs in the clinical lineup have 13 compounds that are at different stages of clinical trials, with a very large number of marine-derived compounds/molecules in the preclinical testing pipeline as well.[2]
The three Food and Drug Administration (FDA) approved the marine-derived drugs currently used in the United States are, cytarabine (Cytosar-UW, DepocytW), vidarabine (Vira-AW), and ziconotide (PrialtW). Various marine drugs in different phases of clinical trials are summarized in [Table 1].[2]
Approved drugs of marine origin
Some of the drugs of marine origin approved for human use in different parts of the world are as follows:
Cytarabine (cytosine arabinoside or arabinosyl cytosine, ara-C)
Cytarabine is a synthetic pyrimidine nucleoside derived from spongothymidine and primarily isolated from a Caribbean sponge species Tethya crypta. It is FDA approved and mainly used in different types of leukemia, including acute myelocytic leukemia, lymphocytic leukemia, meningeal leukemia, and blast crisis phase of chronic myelogenous leukemia.[2]
Vidarabine (adenine arabinoside, ara-A or arabinofuranosyladenine)
Vidarabine is a synthetic purine nucleoside isolated from the Caribbean sponge T. crypta and developed from spongouridine is currently obtained from Streptomyces antibioticus. It is approved by FDA for use in recurrent epithelial keratitis caused by HSV) type 1 and 2, acute kerato-conjunctivitis, and also for superficial keratitis.[2]
Ziconotide
Ziconotide is a synthetic molecule, equivalent to a natural 25-amino acid peptide, v-conotoxin MVIIA. It is originally extracted and purified from the venom of marine snail C. magus, which is a fish-hunting species. Ziconotide has shown potential as an analgesic with a novel mechanism of action.[2] It is approved as an analgesic by FDA.
Trabectedin
A marine natural product extracted from a tunicate species Ecteinascidia turbinata generally inhabitant of Mediterranean and Caribbean Sea. Trabectedin molecule is an alkaloid of tetrahydroisoquinoline class, and it was the first anticancer molecule of marine origin got approval in EU for use in the treatment of soft-tissue sarcoma and in relapsed cases of platinum-sensitive ovarian cancer.[2]
| Marine Drugs in Clinical Phase Iii Trial | | |
Eribulin mesylate (E7389) or halichondrin B
It is a polyether macrolide natural molecule originally extracted from marine sponges, with potent anticancer activity reported in preclinical animal models. Eribulin is a potent molecule which produces irreversible antimitotic activity leading to cell death by apoptotic pathway.[2] On-going Phase III studies are evaluating the comparative clinical efficacy of eribulin versus capecitabine and eribulin versus other preferred treatment choice.
Soblidotin (auristatin PE or TZT-1027)
Is a synthetic derivative of the dolastatin backbone from dolastatin 10. It is a vascular disrupting agent causing the collapse of the vasculature inside the tumor, in addition to its tubulin inhibitory activity. This drug is undergoing trials in clinical Phases I, II, and III with different companies who are trying to use it as a weapon to specific monoclonal antibodies linked via customized peptides.[2]
Tetrodotoxin
A very well known “marine toxin,” and highly substituted guanidine-derivative.[24] It is not an anti-tumor agent, currently in Phase III trials as analgesic against inadequately controlled pain related to the cancer. A Phase II trial is ongoing to assess the efficacy of tetrodotoxin against the neuropathic pain related to chemotherapy-induced peripheral neuropathy.[25]
| Marine-Derived Compounds in Clinical Phase Ii Trial | | |
DMXBA (GTS-21) [3-(2,4-dimethoxybenzylidene)-anabaseine; GTS-21]
It is a synthetic imitative of anabaseine, which is an alkaloid found in many species of aquatic worms of phylum nemertea. DMXBA is reported to be beneficial for the central nervous system, improves cognition and sensory gating deficiency in a variety of laboratory animals.[2] A recent clinical trial of the molecule in Phase II with schizophrenic patients has shown noteworthy improvement in cognitive functions.[2]
Plitidepsin
It is a natural marine depsipeptide, currently obtained by total synthesis. It was primarily isolated from a tunicate Aplidium albicans found in the Mediterranean Sea. Plitidepsin is a highly potent apoptosis inducer with low nanomolar (nM) range of IC50 values. The major toxicity found with most schedules of plitidepsin were muscle toxicity, an increase of transaminases, general fatigue, diarrhea, and cutaneous rash.[2]
Elisidepsin (PM02734)
It is a novel cyclic peptide derived from marine sources and belongs to the Kahalalide family of compounds. It is currently undergoing development in Phase II with primary evidence of antitumor potency with encouraging therapeutic index.[2] It has shown potent in vitro cytotoxic action against diverse human tumor cell lines, which may be because of oncolytic cell death induction instead of apoptotic cell death.[2]
PM00104 (Zalypsis)
It is a novel alkaloid with DNA-binding capacity. It is linked to jorumycin extracted from the Pacific nudibranch's (Jorunna funebris) skin and mucus as well as from renieramiycins extracted from varieties of sponges and tunicates. Preclinical in vivo studies done earlier with these molecules indicated considerably high antitumor activity in cells of breast, prostate and renal cancers with a modest antitumor action on colon cancer cells. Reversible hematological disorders or liver enzymes imbalance were the main toxicities found to be associated with Zalypsis treatment during the Phase I trials.[2]
Plinabulin (NPI-2358)
It is a fully laboratory made analog of the natural product halimide originally derived from marine Aspergillus sp. CNC-139 (from Halimeda lacrimosa) and phenylahistin extracted from Aspergillus ustus.[2] It functions by inhibiting the polymerization of tubulin, which leads to destabilization of the vascular endothelial architecture of the tumor.[26]
ILX-651 (tasidotin or synthadotin)
Its a synthetic derivative of dolastatin-15 and it inhibits assembly of tubulin.[2] It is an orally active drug and has progressed to Phase II trials in different types of cancer. ILX-651 is also under study in preclinical stages for exploring the routes and targets of its actions, including its use in advanced stage refractory neoplasms.[2]
Pseudopterosins
A leading class of diterpene glycosides primarily extracted from the octocoral Pseudopterogorgia elisabethae.[2] Pseudopterosin A is a strong phorbol myristate acetate inhibitor, reported to cause topical inflammation in a mouse model with degranulation of human polymorphonuclear leukocytes and prevents phagosome creation in tetrahymena cells. In a double-blind, Phase II clinical trial, pseudopterosins were found to augment re-epithelialization process with qualitative enhancement in the early wound repair process.[2]
| Marine Drugs in Clinical Phase I Trial | | |
Leconotide (AM-336, ω-conotoxin CVID)
It is a peptide having 27 residues containing 3 CYS-CYS bonds. It is similar to Ziconotide and is undergoing Phase I trials for the treatment of cancer. Although, in initial studies, it is used through intrathecal route (as ziconotide),[27] currently the systemic administration is done.[28],[29]
Enfortumabvedotin
It is used in immunotherapy and it is a combination of a fully human IgG1k antibody and monomethyl auristatin E. It is also known under the code names of AGS-22MSE and AGS-22ME and reported to be currently in a Phase I trial.[23]
Vorsetuzumab mafdotin (SGN-75)
An antibody-drug conjugate, with monomethyl-auristatin F attached to the anti-CD70 monoclonal humanized antibody 1F6.[30] This molecule is currently being evaluated for its efficacy in relapsed and refractory non-Hodgkin's lymphoma in Phase I clinical trials and also in metastatic renal cancer with CD70 epitope expressing cancer cells.[31]
Bryostatin 1
It has in vivo biological active molecule bryostatin 3 (one of the 20 known varieties) isolated from the bryozoan B. neritina. Since the year 2007, at least four Phase I and eight Phase II trials with bryostatin against multiple carcinomas have been reported, with all the studies using a combination with biologicals or cytotoxins. Bryostatin is currently undergoing two Phase I trials for assessment as a treatment for Alzheimer's disease.[2]
Hemiasterlin (E7974)
It's a cytotoxic tripeptide molecule, originally isolated from marine sponges.[2] Dose-limiting toxicities such as neutropenia/febrile neutropenia along with some other adverse events such as general fatigue, nausea, vomiting sensation, and constipation, were reported in the Phase I studies.[2]
Marizomib (NPI-0052, salinosporamide A)
It is a natural compound derived from marine actinomycete Salinispora tropica. Marizomib is a potent and selective inhibitor of the proteasome; a multicatalytic enzyme complex found to be associated with the degradation of nonlysosomal proteins found in cells making it a proven target for the treatment of cancer.[2] Translational biology studies established marizomab activity as a single therapeutic compound against the solid tumor and hematological malignancies (e.g., multiple myelomas). Later studies confirmed the potential of marizomib use in combination with chemotherapy and/or biologics.[2]
| Preclinical Pipeline | | |
The preclinical drug pipeline plays an important role and currently supplying hundreds of novel marine natural compounds postsafety screening every year and continue to support the clinical pipeline with potentially valuable compounds. Since 1974 (when FDA approved 3 marine drugs), it required over 30 years for any other natural product of marine origin to get approved for clinical use.
In the last 5 years, preclinical pharmacology of 262 marine compounds has remained under various stages of study spreading over 35 countries including the USA, they are now part of the preclinical pharmaceutical pipeline.[32] Promising antibacterial, antifungal, antiprotozoal, antitubercular, and antiviral activities have been reported for 102 natural marine compounds.[32] As reported by Mayer et al., around 60 marine compounds have been found to have a potency of immune and nervous systems, some anti-diabetic and anti-inflammatory effects have also been observed. Finally, 68 promising molecules extracted from marine sources were found to interact with an array of molecular targets and receptors, which may probably contribute to develop various pharmacologically active classes of drugs upon more focused studies for confirmation of their mechanism of action.[32] The important agents from the preclinical pipeline are also summarized in [Table 1].
| Anticancer Drugs Developed from Marine Origin: Hope for Future | | |
Targeting the various signal transduction pathways involved in carcinogenesis is one of the best treatment strategies for cancer. Some inhibitors of these pathways derived from the marine organisms have been re-designed, and further studies were done to offset tumor progression and curtail carcinogenesis.[33] Modern anticancer drugs discovery is looking for cytotoxic agents with improved accuracy, efficacy with target specificity and sensitivity.
According to an estimate by Sawadogo et al., in 2011 available promising anticancer compounds of marine origin can be divided into different classes of chemicals majority represented by terpenes and terpenoids (40.5%) following by peptides (19%), macrolides 14.3%), and alkaloids (12%). Among them, 50% are 1st time looked upon as anticancer agents. The majority of these compounds are chemotherapeutic agents (92.7%), and only 7.3% are chemopreventives, which are known as nutraceuticals available in vegetables and fruits.[34] The biological mechanisms involved in the anti-cancer properties of the investigated compounds in Sawadogo et al. study are mainly cell cycle arrest through tubulin inhibitory effect; apoptosis through the various mechanisms such as caspases 3, 8, 7, and 9 activation, MMP depolarization, bib truncation, Bcl-xL, Bax and poly(ADP-ribose) polymerase cleavages; anti-migratory effect through specific inhibitory effect on TRPM7 channels, anti-angiogenic property by inhibition of vascular endothelial growth factor-A secretion; anti-inflammatory effect through the inhibition of COX-2 and iNOS expression.[34] Looking at the possibility of a large number of therapeutic compounds, it may be possible to find out drugs of marine origin for targeted therapy of cancer which is not possible until now with much success.
| Challenges and Future Trends | | |
There are certain major challenges to derive the drugs from marine sources. The variable environmental conditions could result in the production of different metabolite every time from the same organism. A major challenge sometimes faced is that the microorganisms residing in the marine animal, and not the invertebrate marine hosts actually produces the bioactive molecules.[4] Sustainable supply of isolated and identified lead compounds sometimes pose a problem because the lead compound is present only in low quantity and/or technically it becomes very difficult to isolate such compound.[35] For any of intended use (drug, cosmetic, etc.,) of the compound, the required quantity may vary from few grams needed for preclinical drug development and safety studies in different setup; to quantities in kilogram required for clinical study in different phases and many of tons of cosmetics.[4] And the availability of lead compound in such abundance can be a key issue.
The limiting factors for the marine drug developments have been summarized in [Table 2]. Lack of sustainable supply of the candidate compound has sometimes held back further research and development of many extremely potent marine novel compounds. Attempts have been made to beat this hurdle by increased development of synthetic or hemisynthetic analogues derivatives with desired and customized properties, or designing a pharmacophore of lower complexity with easier synthesis method.[36] Identification of a bioactive compound synthesized or hemisynthesized must be done with the reference to the compound derived from the biological source. The structural complexity of the isolated compound and meager yield which is generally faced with marine compounds, may lead to wrong assignment of chemical formula of the compound, its real constitution (planar connectivity), configuration of intramolecular bonds, configuration entirity, and incorrectly assigned one or multiple stereocenters.[37] To overcome the issue of regular supply, the use of natural resources should be under control and need to favor the growth of marine organisms in its natural environment by farming which is also known as “Mariculture.”[37],[38] Another option is to culture the marine organisms under artificial conditions by the process called as “aquaculture” [Table 2].[37],[38]
Martins et al. has very well elucidated the commercial and market issues that are relevant and mostly overlooked in the developmental process of new natural products.[4] Some of the points that need to be addressed from the very early development phase are as follows: (i) What are the potential industrial use of the product and need of that particular activity of the compound in the market? (ii) What will be the final cost per kg for the final bioactive material? (iii) The desired formulation and preferred route of administration of the compound; (iv) What process of manufacture is being used and whether the supply is sustainable? and finally (v) How will the product reach the market chain?
Some limitations of the marine drug development includes the development of universal expression systems for biosynthesis of small molecules with high-yield, development of genetic tools to access the in vivo potential of cultured marine microorganisms, and the regulatory arousing of silent biosynthetic pathways for small molecule discovery.[38]
The subsequent levels of development of drugs comprises in vivo evaluations of safety and efficacy in animal models, determination of the mechanism and site of action, development of structure-activity relationships, formulation and characterization of pharmacokinetics parameters and pharmaceutical properties including improvements through the use of medicinal chemistry.[38]
Initial efforts in marine natural products chemistry have largely focused on collecting metabolites from most easily collected species.[30] Minor metabolites present in very small quantities are a challenge for analytical and biological evaluations. In silico screening programs can be useful to understand the natural scaffolding of these minor drug candidates better.[30] Scientists are making efforts to improve the access to minor metabolites through technological advancements, such as increasingly widespread use of NMR microcryogenic and capillary flow-probes, biological assays in increasingly smaller volumes such as in 384- and 1534-well plate formats and enhancements of the methods as well as informatics and logistics associated with mass spectrometry.[39] Another area of improvement in marine drug discovery programs is the biological assay methods of extracts, fractions, and pure compounds. Assay-based isolation design for marine natural products has the potential for automation that may result in dramatic improvement in the way by which different classes of natural products are discovered in nature.[38]
Looking at the vast potential and leads, there are several Institutes in India as well as all over the world, concentrating on research and training in marine pharmacology field. Most of the research institutes are concentrating on the discovery of potential novel compounds from marine organisms, extraction/isolation, their safety and efficacy assessment and large-scale commercial production. Some of the institutes doing research and universities imparting training on marine pharmacology in and [Table 3] and [Table 4]outside India are mentioned in respectively. | Table 3: Institutes/universities offering training or research on marine drugs in India
Click here to view |
 | Table 4: Institutes/Universities offering training/research on marine drugs outside India
Click here to view |
| Conclusions | | |
Marine environment has become a promising source of natural products, molecules, and drugs of therapeutic use. Having enormous varieties with a great diversity of organism and virgin areas of marine life, the prospects of yielding more novel products from the sea is enormous. The curiosity of science and industry has established the oceans as a prospective source for new potential drug leads. Scientists have come up with drugs of various categories out of which anticancer, anti-inflammatory, analgesics, and antivirals are the most important to mention. These lead molecules are in different stages of preclinical and clinical testing stages around the world. Many drugs from marine sources have a promising effect on several chronic and unbeatable diseases like cancer. They may prove to open up a new chapter of making the treatment of chronic diseases cheaper and successful.
After identification, extraction, and large scale production of promising marine natural products of therapeutic uses, their marketing and commercial exploitation of potential is dependent on the results of preclinical and clinical data. The current screening for active natural products should be increased along with a large and rapid random screening method. Several research institutes and universities are working in this field to develop new moieties and train people to work in this area. The technology should be targeted optimally for drug research, approvals, and launches. The medical pharmacologist from India should consider taking up the further research in marine pharmacology to help our country in new drug developments. The importance of Marine Pharmacology is summarized in [Figure 1]. The evolution of marine pharmacology as a specialty in India will help us optimizing the use of rich marine resources around our beautiful country gifted with a vast coastline [Figure 1].
Acknowledgment
Author acknowledge the support received from Dr. Namrata Singh for reviewing and editing the manuscript.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4]
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Hymenialdisine: A Marine Natural Product That Acts on Both Osteoblasts and Osteoclasts and Prevents Estrogen-Dependent Bone Loss in Mice |
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| Qingqing Wang, Delong Chen, Haiming Jin, Zhen Ye, Chao Wang, Kai Chen, Vincent Kuek, Ke Xu, Heng Qiu, Peng Chen, Dezhi Song, Jinmin Zhao, Qian Liu, Rohan A. Davis, Fangming Song, Jiake Xu | | Journal of Bone and Mineral Research. 2020; 35(8): 1582 | | [Pubmed] | [DOI] | | | 69 |
Total Synthesis of Natural Lembehyne C and Investigation of Its Cytotoxic Properties |
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Urupocidin C: a new marine guanidine alkaloid which selectively kills prostate cancer cells via mitochondria targeting |
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Immune-modulating and anti-inflammatory marine compounds against cancer |
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| Cristina Florean, Mario Dicato, Marc Diederich | | Seminars in Cancer Biology. 2020; | | [Pubmed] | [DOI] | | | 72 |
Chemical space and diversity of seaweed metabolite database (SWMD): A cheminformatics study |
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Metabolomic tools used in marine natural product drug discovery |
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A permissive approach for optimization of L-glutaminase production using wheat bran as supporting substrate and assessment of its cytotoxic potentialities |
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A marine fungus-derived nitrobenzoyl sesquiterpenoid suppresses receptor activator of NF-?B ligand-induced osteoclastogenesis and inflammatory bone destruction |
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| Yanhui Tan, Wende Deng, Yueyang Zhang, Minhong Ke, Binhua Zou, Xiaowei Luo, Jianbin Su, Yiyuan Wang, Jialan Xu, Kutty Selva Nandakumar, Yonghong Liu, Xuefeng Zhou, Xiaojuan Li | | British Journal of Pharmacology. 2020; 177(18): 4242 | | [Pubmed] | [DOI] | | | 76 |
Antidiabetic activity in vitro and in vivo of BDB, a selective inhibitor of protein tyrosine phosphatase 1B, from
Rhodomela confervoides
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Preclinical and Clinical Studies on Bryostatins, A Class of Marine-Derived Protein Kinase C Modulators: A Mini-Review |
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| Rinky Raghuvanshi, Sandip B. Bharate | | Current Topics in Medicinal Chemistry. 2020; 20(12): 1124 | | [Pubmed] | [DOI] | | | 78 |
Exploring Antimicrobials from the Flora and Fauna of Marine: Opportunities and Limitations |
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Science, Diplomacy, and the Red Sea’s Unique Coral Reef: It’s Time for Action |
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Effects of Diet on the Biochemical Properties of Limulus Amebocyte Lysate From Horseshoe Crabs in an Aquaculture Setting |
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| Rachel Tinker-Kulberg, Anthony Dellinger, Terry E. Brady, Lee Robertson, Melinda K. M. Goddard, John Bowzer, Sarah K. Abood, Christopher Kepley, Kristen Dellinger | | Frontiers in Marine Science. 2020; 7 | | [Pubmed] | [DOI] | | | 81 |
Marine Natural Products with High Anticancer Activities |
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| Dario Matulja, Karlo Wittine, Nela Malatesti, Sylvain Laclef, Maris Turks, Maria Kolympadi Markovic, Gabriela Ambrožic, Dean Markovic | | Current Medicinal Chemistry. 2020; 27(8): 1243 | | [Pubmed] | [DOI] | | | 82 |
Marine Algal Antioxidants as Potential Vectors for Controlling Viral Diseases |
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From Seabed to Bedside: A Review on Promising Marine Anticancer Compounds |
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| Edina Wang, Maria Alba Sorolla, Priya Darshini Gopal Krishnan, Anabel Sorolla | | Biomolecules. 2020; 10(2): 248 | | [Pubmed] | [DOI] | | | 84 |
Cardiovascular Active Peptides of Marine Origin with ACE Inhibitory Activities: Potential Role as Anti-Hypertensive Drugs and in Prevention of SARS-CoV-2 Infection |
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| Marco Festa, Clementina Sansone, Christophe Brunet, Fabio Crocetta, Luisa Di Paola, Michele Lombardo, Antonino Bruno, Douglas M. Noonan, Adriana Albini | | International Journal of Molecular Sciences. 2020; 21(21): 8364 | | [Pubmed] | [DOI] | | | 85 |
Deep Hypersaline Anoxic Basins as Untapped Reservoir of Polyextremophilic Prokaryotes of Biotechnological Interest |
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| Stefano Varrella, Michael Tangherlini, Cinzia Corinaldesi | | Marine Drugs. 2020; 18(2): 91 | | [Pubmed] | [DOI] | | | 86 |
CYC31, A Natural Bromophenol PTP1B Inhibitor, Activates Insulin Signaling and Improves Long Chain-Fatty Acid Oxidation in C2C12 Myotubes |
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| Jiao Luo, Yufei Hou, Mengyue Xie, Wanli Ma, Dayong Shi, Bo Jiang | | Marine Drugs. 2020; 18(5): 267 | | [Pubmed] | [DOI] | | | 87 |
Marine Biocompounds for Neuroprotection—A Review |
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| Adrian Florian Bala?a, Cristina Chircov, Alexandru Mihai Grumezescu | | Marine Drugs. 2020; 18(6): 290 | | [Pubmed] | [DOI] | | | 88 |
Exploring the Mechanism of Flaccidoxide-13-Acetate in Suppressing Cell Metastasis of Hepatocellular Carcinoma |
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| Yu-Jen Wu, Wen-Chi Wei, Guo-Fong Dai, Jui-Hsin Su, Yu-Hwei Tseng, Tsung-Chang Tsai | | Marine Drugs. 2020; 18(6): 314 | | [Pubmed] | [DOI] | | | 89 |
New Cytotoxic Cerebrosides from the Red Sea Cucumber Holothuria spinifera Supported by In-Silico Studies |
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| Reda F. A. Abdelhameed, Enas E. Eltamany, Dina M. Hal, Amany K. Ibrahim, Asmaa M. AboulMagd, Tarfah Al-Warhi, Khayrya A. Youssif, Adel M. Abd El-kader, Hashim A. Hassanean, Shaimaa Fayez, Gerhard Bringmann, Safwat A. Ahmed, Usama Ramadan Abdelmohsen | | Marine Drugs. 2020; 18(8): 405 | | [Pubmed] | [DOI] | | | 90 |
Marine Cyanobacteria and Microalgae Metabolites—A Rich Source of Potential Anticancer Drugs |
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| Arijit Mondal, Sankhadip Bose, Sabyasachi Banerjee, Jayanta Kumar Patra, Jai Malik, Sudip Kumar Mandal, Kaitlyn L. Kilpatrick, Gitishree Das, Rout George Kerry, Carmela Fimognari, Anupam Bishayee | | Marine Drugs. 2020; 18(9): 476 | | [Pubmed] | [DOI] | | | 91 |
Marine Antithrombotics |
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| Rohini Dwivedi, Vitor H. Pomin | | Marine Drugs. 2020; 18(10): 514 | | [Pubmed] | [DOI] | | | 92 |
Chemical Defense in Marine Organisms |
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| Chiara Lauritano, Adrianna Ianora | | Marine Drugs. 2020; 18(10): 518 | | [Pubmed] | [DOI] | | | 93 |
Interaction of Thalassia testudinum Metabolites with Cytochrome P450 Enzymes and Its Effects on Benzo(a)pyrene-Induced Mutagenicity |
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| Livan Delgado-Roche, Rebeca Santes-Palacios, José A. Herrera, Sandra L. Hernández, Mario Riera, Miguel D. Fernández, Fernando Mesta, Gabino Garrido, Idania Rodeiro, Jesús Javier Espinosa-Aguirre | | Marine Drugs. 2020; 18(11): 566 | | [Pubmed] | [DOI] | | | 94 |
Sustainable Low-Volume Analysis of Environmental Samples by Semi-Automated Prioritization of Extracts for Natural Product Research (SeaPEPR) |
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| Riyanti, Michael Marner, Christoph Hartwig, Maria Patras, Stevy Wodi, Frets Rieuwpassa, Frans Ijong, Walter Balansa, Till Schäberle | | Marine Drugs. 2020; 18(12): 649 | | [Pubmed] | [DOI] | | | 95 |
Bioactive Compounds from Marine Heterobranchs |
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| Conxita Avila, Carlos Angulo-Preckler | | Marine Drugs. 2020; 18(12): 657 | | [Pubmed] | [DOI] | | | 96 |
Broad spectrum antimicrobial activities from spore-forming bacteria isolated from the Vietnam Sea |
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| Khanh Minh Chau, Dong Van Quyen, Joshua M. Fraser, Andrew T. Smith, Thi Thu Hao Van, Robert J. Moore | | PeerJ. 2020; 8: e10117 | | [Pubmed] | [DOI] | | | 97 |
Microalgae with Immunomodulatory Activities |
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| Riccio, Lauritano | | Marine Drugs. 2019; 18(1): 2 | | [Pubmed] | [DOI] | | | 98 |
Draft Genome Sequence of
Bacillus
sp. Strain 007/AIA-02/001, Isolated from the Marine Sponge
Coelocarteria singaporensis
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| Ji Fa Marshall Ong, Hui Chin Goh, Lik Tong Tan, David Rasko | | Microbiology Resource Announcements. 2019; 8(35) | | [Pubmed] | [DOI] | | | 99 |
Draft Genome Sequence of
Mycolicibacterium
sp. Strain 018/SC-01/001, Isolated from the Marine Sponge
Iotrochota
sp
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| Ji Fa Marshall Ong, Lik Tong Tan, David Rasko | | Microbiology Resource Announcements. 2019; 8(42) | | [Pubmed] | [DOI] | | | 100 |
Effectiveness of methanol extract hydroid aglaophenia cupressina lamoureoux as antimicrobial in resistant Methicilline Staphylococcus Aureus (MRSA), Shigella sp., Malassezia furfur, and Candida albicans |
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| E Johannes, M Litaay, N Haedar, V V Randan, N S Rupang, M Tuwo | | Journal of Physics: Conference Series. 2019; 1341(2): 022015 | | [Pubmed] | [DOI] | | | 101 |
Satellite sensor requirements for monitoring essential biodiversity variables of coastal ecosystems |
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| Frank E. Muller-Karger, Erin Hestir, Christiana Ade, Kevin Turpie, Dar A. Roberts, David Siegel, Robert J. Miller, David Humm, Noam Izenberg, Mary Keller, Frank Morgan, Robert Frouin, Arnold G. Dekker, Royal Gardner, James Goodman, Blake Schaeffer, Bryan A. Franz, Nima Pahlevan, Antonio G. Mannino, Javier A. Concha, Steven G. Ackleson, Kyle C. Cavanaugh, Anastasia Romanou, Maria Tzortziou, Emmanuel S. Boss, Ryan Pavlick, Anthony Freeman, Cecile S. Rousseaux, John Dunne, Matthew C. Long, Eduardo Klein, Galen A. McKinley, Joachim Goes, Ricardo Letelier, Maria Kavanaugh, Mitchell Roffer, Astrid Bracher, Kevin R. Arrigo, Heidi Dierssen, Xiaodong Zhang, Frank W. Davis, Ben Best, Robert Guralnick, John Moisan, Heidi M. Sosik, Raphael Kudela, Colleen B. Mouw, Andrew H. Barnard, Sherry Palacios, Collin Roesler, Evangelia G. Drakou, Ward Appeltans, Walter Jetz | | Ecological Applications. 2018; 28(3): 749 | | [Pubmed] | [DOI] | | | 102 |
Plant-derived antimicrobials to fight against multi-drug-resistant human pathogens |
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Antibacterial activity of the Saudi Red Sea sponges against Gram-positive pathogens |
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| Rafat Afifi,Omar F. Khabour | | Journal of King Saud University - Science. 2017; | | [Pubmed] | [DOI] | | | 104 |
Total synthesis and structural revision of a mangrove alkaloid |
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| Michael T. Green,Gary R. Peczkowski,Aneesa J. Al-Ani,Sophie L. Benjamin,Nigel S. Simpkins,Alan M. Jones | | RSC Adv.. 2017; 7(77): 48754 | | [Pubmed] | [DOI] | | | 105 |
The Natural Antiangiogenic Compound AD0157 Induces Caspase-Dependent Apoptosis in Human Myeloid Leukemia Cells |
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| Melissa García-Caballero,Beatríz Martínez-Poveda,Miguel A. Medina,Ana R. Quesada | | Frontiers in Pharmacology. 2017; 8 | | [Pubmed] | [DOI] | | | 106 |
Crude extract and solvent fractions of Calystegia soldanella induce G1 and S phase arrest of the cell cycle in HepG2 cells |
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| Jung Im Lee,In-Hye Kim,Taek-Jeong Nam | | International Journal of Oncology. 2017; 50(2): 414 | | [Pubmed] | [DOI] | | | 107 |
An Updated Review on Marine Anticancer Compounds: The Use of Virtual Screening for the Discovery of Small-Molecule Cancer Drugs |
|
| Verónica Ruiz-Torres,Jose Encinar,María Herranz-López,Almudena Pérez-Sánchez,Vicente Galiano,Enrique Barrajón-Catalán,Vicente Micol | | Molecules. 2017; 22(7): 1037 | | [Pubmed] | [DOI] | | | 108 |
Marine Fish Proteins and Peptides for Cosmeceuticals: A Review |
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| Jayachandran Venkatesan,Sukumaran Anil,Se-Kwon Kim,Min Shim | | Marine Drugs. 2017; 15(6): 143 | | [Pubmed] | [DOI] | | | 109 |
Two New Oxodolastane Diterpenes from the Jamaican Macroalga Canistrocarpus cervicornis |
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| Sanjay Campbell,JeAnn Murray,Rupika Delgoda,Winklet Gallimore | | Marine Drugs. 2017; 15(6): 150 | | [Pubmed] | [DOI] | | | 110 |
Evaluating the Effects of an Organic Extract from the Mediterranean Sponge Geodia cydonium on Human Breast Cancer Cell Lines |
|
| Susan Costantini,Eliana Guerriero,Roberta Teta,Francesca Capone,Alessia Caso,Angela Sorice,Giovanna Romano,Adrianna Ianora,Nadia Ruocco,Alfredo Budillon,Valeria Costantino,Maria Costantini | | International Journal of Molecular Sciences. 2017; 18(10): 2112 | | [Pubmed] | [DOI] | | | 111 |
Marine Organisms with Anti-Diabetes Properties |
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| Chiara Lauritano,Adrianna Ianora | | Marine Drugs. 2016; 14(12): 220 | | [Pubmed] | [DOI] | |
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