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Marine pharmacognosy is the investigation and identification of medically important plants and animals in the marine environment. It is a sub branch of terrestrial pharmacognosy. Generally the drugs are obtained from the marine species of bacteria, virus, algae, fungi and sponges. It is a relatively new field of study in western medicine, although many marine organisms were used in traditional Chinese medicine. It was not until 2004 that the first FDA approval of a drug came directly from the sea: ziconotide, which was isolated from a marine cone snail.
With 79% of the Earth's surface covered by water, research into the chemistry of marine organisms is relatively unexplored and represents a vast resource for new medicines to combat major diseases such as cancer, AIDS or malaria. Research typically focuses on sessile organisms or slow moving animals because of their inherent need for chemical defenses.
Standard research involves an extraction of the organism in a suitable solvent followed by either an assay of this crude extract for a particular disease target or a rationally guided isolation of new chemical compounds using standard chromatography techniques.
Over 70% of the Earth's surface is covered by oceans which contain 95% of the Earth's biosphere. [1] It was over 3500 million years ago that organisms first appeared in the sea. Over time, they have evolved many different mechanisms to survive the various harsh environments which include extreme temperatures, salinity, pressure, different levels of aeration and radiation, overcoming effects of mutation, and combating infection, fouling and overgrowth by other organisms. [1] [2] Adaptations to survive the different environments could be by physical or chemical adaptation. Organisms with no apparent physical defense, like sessile organisms, are believed to have evolved chemical defenses to protect themselves. [1] It is also believed that the compounds would have to be extremely potent due to the dilution effect of seawater. This has been described to be analogues to pheromones but with the purpose of repelling instead of attracting. [3] As well, predators have evolved chemical weapons in order to paralyze or kill prey. Conus magus is an example of a cone snail that has a poisoned harpoon-like projectile which it uses to paralyze prey like small fish. [4] Some organisms, like the Viperfish, are believed to attract small fish or prey by using its photophore. [5]
Many different marine organisms have been explored for bioactive compounds. Some vertebrate animals include fish, sharks and snakes. Some examples of invertebrates are sponges, coelenterates, tunicates, echinoderms, corals, algae, molluscs and bryozoans. Some microorganisms include bacteria, fungi and cyanobacteria. [6]
There is an ongoing debate on what organisms are the actual true producers of some compounds. About 40% of the biomass of sponges can be from microorganisms. It's not surprising that some compounds may actually be produced by symbiotic microorganisms rather than the host.
Marine environments are considered more biologically diverse than terrestrial environments. [4] [7] Thirty-two different animal phyla are represented in the oceans of the 33 recognized phyla. Fifteen different phyla are represented only in marine environments, while only 1 is exclusively terrestrial. Marine phyla also contain functionally unique organisms such as filter feeders and sessile organisms which have no terrestrial counterpart. Also, marine autotrophs are more diverse than their terrestrial counterparts this is extremely important. Marine autotrophs are believed to stem from at least 8 ancient clades while terrestrial organisms mainly stem from one clade, Embyrophyta. [7] Marine environments may contain over 80% of the world's plant and animal species. [6] The diversity of coral reefs can be extraordinary with species diversity reaching 1000 species per meter squared. The greatest marine tropical biodiversity is reported to be in the Indo-Pacific Ocean. [8]
Collecting marine samples can range from very simple and inexpensive to very complicated expensive. Samples from near or on shores are readily accessible via beach combing, wading or snorkeling. [3] [9] Sample collection from deep water can be completed via dredging however, this is a very invasive technique which destroys the local habitat, does not allow for repeated sampling from the same location and compromises sample integrity. Corers can be used for sediment sample collection from deep locations quickly, easily and inexpensively. SCUBA diving was introduced in the 1940s however, [3] it was not widely used until it became popular in the 1970s. SCUBA diving is limited in the duration that divers can spend underwater when conducted from the surface. If prolonged dives were necessary, an underwater laboratory could be used. Aquarius is the only underwater laboratory dedicated to marine science. [10] For sample collection from depths that cannot be achieved by SCUBA diving, submersibles may be used. Sample collection by submersibles can be extremely expensive with costs for a submersible, support ship, technicians and support staff ranging between $10,000 to $45,000 per day. [11]
For the isolation of biologically active compounds from organisms, several different steps need to be completed. The different steps required to obtain a biologically active compound are: Extraction, chromatographic purification, dereplication, structure elucidation and bioassay testing. The steps do not have to follow that particular order and many steps may be completed simultaneously. In the first step, the sample may be triturated and extracted with a suitable solvent or macerated. Some solvents used are methanol:chloroform, ethanol, acetonitrile, or others. The purpose is to remove organic compounds that have a medium polarity which are considered more "drug-like". Ideally, polar compounds like salts, peptides, sugars as well as very non-polar compounds like lipids are left behind to simplify chromatography since they are not generally considered "drug-like". Drying of the sample could be completed before extraction by lyophilisation to remove any excess water and therefore limit the amount of highly polar compounds extracted.
The next step depends on the methodology of individual laboratories. Bioassay-guided fractionation is a common method to find biologically active compounds. This involves testing the crude extract or preliminary fractions from chromatography in an assay or multiple assays, determining what fractions or crude extracts show activity in the specific assays, and further fractionating the active fractions or extracts. This step is than repeated where the new fractions are tested and the active fractions are further fractionated. This continues until the fraction only contains one compound. Dereplication is ideally performed as early as possible to determine if the active compound has been previously reported in order to prevent "rediscovering" a compound. This can be performed using Liquid Chromatography- Mass Spectrometry (LC-MS) data or Nuclear Magnetic Resonance (NMR) data obtained in the biological assay-guided process and than comparing the information to that found in databases of previously reported compounds.
Structure elucidation is performed by using NMR data obtained of the compound and High Resolution Mass Spectrometry (HR-MS) Data. Tandem Mass Spectrometry can also be useful, especially for large molecules like glycolipids, proteins, polysaccharides or peptides. Completed characterization for publication purposes may require Infrared (IR), Ultraviolet-visible (UV-vis), specific rotation and melting point data. Obtaining a crystal structure via X-ray crystallography can greatly accelerate and simplify structure elucidation however, obtaining crystals can be quite difficult.
There are many different bioassays available for testing. There are anticancer, antimicrobial, antiviral, anti-inflammatory, antiparasitic, anticholesterolemic, and many other differ assays. For MTT assay and cytosolic Lactate dehydrogenase (LDH) release are common cytotoxicity or cell viability assays.
A common problem that plagues drug development is obtaining a sustainable supply of the compound. Compounds isolated from invertebrates can be difficult to obtain in sufficient quantity for clinical trials. Synthesis is an alternate source of the compound of interest if the compound is simple otherwise, it is generally not a viable alternative. Aqua culture is another alternative if the organism is readily grown otherwise, it may not be good sustainable source of a compound. Also, the small quantity the compound is usually found in from organisms makes this alternative even more expensive. For example, ET-743 (INN name trabectedin, brand name Yondelis) can be isolated from the tunicate Ecteinascidia turbinata with a yield of 2 g per ton. [3] This would require thousands of tons of tunicate to be grown and extracted to produce the kilograms of ET-743 that would be required for the treatment of thousands of people. Some success has been had in producing compounds of interest from microorganisms. Microorganisms can be used as a sustainable source for the production of compounds of interest. They can also be used for the production of intermediates so that semisynthesis can be used to produce the final compound. This has been achieved for ET-743 with the production of the intermediate Safracin B from Pseudomonas fluoresens and the subsequent semisynthesis into ET-743. This is currently the industrial production method for the production of Yondelis. [12]
Clinical Status | Compound Name | Trademark | Marine Organismα | Chemical Class | Molecular Target | Clinical Trialsβ | Disease Area |
---|---|---|---|---|---|---|---|
FDA-Approved | Cytarabine (Ara-C) | Cytosar-U | Sponge | Nucleoside | DNA Polymerase | >50/711 | Cancer |
Vidarabine (Ara-A) | Vira-A | Sponge | Nucleoside | Viral DNA Polymerase | 0 | Antiviral | |
Ziconotide | Prialt | Cone Snail | Peptide | N-Type Ca2+ Channel | 2/5 | Analgesic | |
Eribulin Mesylate (E7389) | Halaven | Sponge | Macrolide | Microtubules | 19/27 | Cancer | |
Omega-3-Fatty Acid Ethyl Esters | Lovaza | Fish | Omega-3 Fatty Acids | Triglyceride-Synthesizing Enzymes | 45/94 | Hypertriglyceridemia | |
Trabectedin (ET-743) EU Approved only | Yondelis | Tunicate | Alkaloid | Minor Groove of DNA | 17/34 | Cancer | |
Phase III | Brentuximab Vedotin (SGN-35) | Adcetris | Mollusk | Antibody-Drug Conjugate (MM Auristatin E) | CD30 and Microtubules | 9/19 | Cancer |
Plitidepsin | Aplidin | Tunicate | Depsipeptide | Rac1 and JNK Activation | 1/7 | Cancer | |
Phase II | DMXBA (GTS-21) | N/A | Worm | Alkaloid | Alpha-7 Nicotinic Acetylcholine Receptor | 0/3 | Cognition, Schizophrenia |
Plinabulin (NPI 2358) | N/A | Fungus | Diketopiperazine | Microtubules and JNK Stress Protein | 1/2 | Cancer | |
Elisidepsin | Irvalec | Mollusk | Depsipeptide | Plasma Membrane Fluidity | 1/2 | Cancer | |
PM00104 | Zalypsis | Nudibranch | Alkaloid | DNA-Binding | 2/3 | Cancer | |
Glembatumumab Vedotin (CDX-011) | N/A | Mollusk | Antibody Drug Conjugate (MM Auristatin E) | Glycoprotein NMB and Microtubules | 1/3 | Cancer | |
Phase I | Marizomib (Salinosporamide A) | N/A | Bacterium | Beta-Lactone-Gamma Lactam | 20S Proteasome | 4/4 | Cancer |
PM01183 | N/A | Tunicate | Alkaloid | Minor Groove of DNA | N/A | Cancer | |
SGN-75 | N/A | Mollusk | Antibody Drug Conjugate (MM Auristatin F) | CD70 and Microtubules | 2/2 | Cancer | |
ASG-5ME | N/A | Mollusk | Antibody Drug Conjugate (MM auristatin E) | ASG-5 and Microtubules | 2/2 | Cancer | |
Hemiasterlin (E7974) | N/A | Sponge | Tripeptide | Microtubules | 0/3 | Cancer | |
Bryostatin 1 | N/A | Bryozoa | Polyketide | Protein Kinase C | 0/38 | Cancer, Alzheimers | |
Pseudopterosins | N/A | Soft Coral | Diterpene Glycoside | Eicosanoid Metabolism | N/A | Wound Healing |
αIncludes natural products or natural product derivatives or analogues; βNumber of active trials/number of total trials from http://www.clinicaltrials.gov/ as of July 2011
Bioprospecting is the exploration of natural sources for small molecules, macromolecules and biochemical and genetic information that could be developed into commercially valuable products for the agricultural, aquaculture, bioremediation, cosmetics, nanotechnology, or pharmaceutical industries. In the pharmaceutical industry, for example, almost one third of all small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) between 1981 and 2014 were either natural products or compounds derived from natural products.
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compounds can also become xenobiotics if they are taken up by another organism, such as the uptake of natural human hormones by fish found downstream of sewage treatment plant outfalls, or the chemical defenses produced by some organisms as protection against predators. The term xenobiotic is also used to refer to organs transplanted from one species to another.
Protein purification is a series of processes intended to isolate one or a few proteins from a complex mixture, usually cells, tissues or whole organisms. Protein purification is vital for the specification of the function, structure and interactions of the protein of interest. The purification process may separate the protein and non-protein parts of the mixture, and finally separate the desired protein from all other proteins. Ideally, to study a protein of interest, it must be separated from other components of the cell so that contaminants will not interfere in the examination of the protein of interest's structure and function. Separation of one protein from all others is typically the most laborious aspect of protein purification. Separation steps usually exploit differences in protein size, physico-chemical properties, binding affinity and biological activity. The pure result may be termed protein isolate.
A biogenic substance is a product made by or of life forms. While the term originally was specific to metabolite compounds that had toxic effects on other organisms, it has developed to encompass any constituents, secretions, and metabolites of plants or animals. In context of molecular biology, biogenic substances are referred to as biomolecules. They are generally isolated and measured through the use of chromatography and mass spectrometry techniques. Additionally, the transformation and exchange of biogenic substances can by modelled in the environment, particularly their transport in waterways.
Pharmacognosy is the study of crude drugs obtained from medicinal plants, animals, fungi, and other natural sources. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical, and biological properties of drugs, drug substances, or potential drugs or drug substances of natural origin as well as the search for new drugs from natural sources".
Fractionation is a separation process in which a certain quantity of a mixture is divided during a phase transition, into a number of smaller quantities (fractions) in which the composition varies according to a gradient. Fractions are collected based on differences in a specific property of the individual components. A common trait in fractionations is the need to find an optimum between the amount of fractions collected and the desired purity in each fraction. Fractionation makes it possible to isolate more than two components in a mixture in a single run. This property sets it apart from other separation techniques.
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical synthesis and have played a central role in the development of the field of organic chemistry by providing challenging synthetic targets. The term natural product has also been extended for commercial purposes to refer to cosmetics, dietary supplements, and foods produced from natural sources without added artificial ingredients.
Ex vivo literally means that which takes place outside an organism. In science, ex vivo refers to experimentation or measurements done in or on tissue from an organism in an external environment with minimal alteration of natural conditions.
In biology, detritus is dead particulate organic material, as distinguished from dissolved organic material. Detritus typically includes the bodies or fragments of bodies of dead organisms, and fecal material. Detritus typically hosts communities of microorganisms that colonize and decompose it. In terrestrial ecosystems it is present as leaf litter and other organic matter that is intermixed with soil, which is denominated "soil organic matter". The detritus of aquatic ecosystems is organic substances that is suspended in the water and accumulates in depositions on the floor of the body of water; when this floor is a seabed, such a deposition is denominated "marine snow".
Trabectedin, sold under the brand name Yondelis, is an antitumor chemotherapy medication for the treatment of advanced soft-tissue sarcoma and ovarian cancer.
Chungtia is an Ao Naga village in Nagaland, India. It lies in the Ongpangkong range and is located 16 km north-west of Mokokchung. The Mokokchung-Mariani Highway passes through its eastern corner. It is located at an altitude of 3,362 feet (1,025 m) above sea level.
Marine invertebrates are the invertebrates that live in marine habitats. Invertebrate is a blanket term that includes all animals apart from the vertebrate members of the chordate phylum. Invertebrates lack a vertebral column, and some have evolved a shell or a hard exoskeleton. As on land and in the air, marine invertebrates have a large variety of body plans, and have been categorised into over 30 phyla. They make up most of the macroscopic life in the oceans.
3-Alkylpyridinium (3-AP) compounds are natural chemical compounds that are found in marine sponges belonging to the order Haplosclerida. Some polymers derived from 3-APs are anticholinesterase agents and show hemolytic and cytotoxic activities. More than 70 structurally different 3-APs have been isolated from marine sponges. However, not all such sponges contain 3-AP compounds. Variation in content of 3-APs has been detected even within a single sponge species collected from different geographical area. Although 3-APs look structurally quite simple, the structure elucidation by NMR spectroscopy is complicated by the fact that most of the methylene groups in the alkyl chains show the same chemical shift. Therefore, the 3-APs are an ideal test case for a combined approach of NMR spectroscopy and mass spectrometry.
Sea sponge aquaculture is the process of farming sea sponges under controlled conditions. It has been conducted in the world's oceans for centuries using a number of aquaculture techniques. There are many factors such as light, salinity, pH, dissolved oxygen and the accumulation of waste products that influence the growth rate of sponges. The benefits of sea sponge aquaculture are realised as a result of its ease of establishment, minimum infrastructure requirements and the potential to be used as a source of income for populations living in developing countries. Sea sponges are produced on a commercial scale to be used as bath sponges or to extract biologically active compounds which are found in certain sponge species. Techniques such as the rope and mesh bag method are used to culture sponges independently or within an integrated multi-trophic aquaculture system setting. One of the only true sustainable sea sponges cultivated in the world occur in the region of Micronesia, with a number of growing and production methods used to ensure and maintain the continued sustainability of these farmed species.
Ecteinascidia turbinata, commonly known as the mangrove tunicate, is a species of sea squirt species in the family Perophoridae. It was described to science in 1880 by William Abbott Herdman. The cancer drug trabectedin is isolated from E. turbinata.
Phycotoxins are complex allelopathic chemicals produced by eukaryotic and prokaryotic algal secondary metabolic pathways. More simply, these are toxic chemicals synthesized by photosynthetic organisms. These metabolites are not harmful to the producer but may be toxic to either one or many members of the marine food web. This page focuses on phycotoxins produced by marine microalgae; however, freshwater algae and macroalgae are known phycotoxin producers and may exhibit analogous ecological dynamics. In the pelagic marine food web, phytoplankton are subjected to grazing by macro- and micro-zooplankton as well as competition for nutrients with other phytoplankton species. Marine bacteria try to obtain a share of organic carbon by maintaining symbiotic, parasitic, commensal, or predatory interactions with phytoplankton. Other bacteria will degrade dead phytoplankton or consume organic carbon released by viral lysis. The production of toxins is one strategy that phytoplankton use to deal with this broad range of predators, competitors, and parasites. Smetacek suggested that "planktonic evolution is ruled by protection and not competition. The many shapes of plankton reflect defense responses to specific attack systems". Indeed, phytoplankton retain an abundance of mechanical and chemical defense mechanisms including cell walls, spines, chain/colony formation, and toxic chemical production. These morphological and physiological features have been cited as evidence for strong predatory pressure in the marine environment. However, the importance of competition is also demonstrated by the production of phycotoxins that negatively impact other phytoplankton species. Flagellates are the principle producers of phycotoxins; however, there are known toxigenic diatoms, cyanobacteria, prymnesiophytes, and raphidophytes. Because many of these allelochemicals are large and energetically expensive to produce, they are synthesized in small quantities. However, phycotoxins are known to accumulate in other organisms and can reach high concentrations during algal blooms. Additionally, as biologically active metabolites, phycotoxins may produce ecological effects at low concentrations. These effects may be subtle, but have the potential to impact the biogeographic distributions of phytoplankton and bloom dynamics.
A polar organic chemical integrative sampler (POCIS) is a passive sampling device which allows for the in situ collection of a time-integrated average of hydrophilic organic contaminants developed by researchers with the United States Geological Survey in Columbia, Missouri. POCIS provides a means for estimating the toxicological significance of waterborne contaminants. The POCIS sampler mimics the respiratory exposure of organisms living in the aquatic environment and can provide an understanding of bioavailable contaminants present in the system. POCIS can be deployed in a wide range of aquatic environments and is commonly used to assist in environmental monitoring studies.
Microbial symbiosis in marine animals was not discovered until 1981. In the time following, symbiotic relationships between marine invertebrates and chemoautotrophic bacteria have been found in a variety of ecosystems, ranging from shallow coastal waters to deep-sea hydrothermal vents. Symbiosis is a way for marine organisms to find creative ways to survive in a very dynamic environment. They are different in relation to how dependent the organisms are on each other or how they are associated. It is also considered a selective force behind evolution in some scientific aspects. The symbiotic relationships of organisms has the ability to change behavior, morphology and metabolic pathways. With increased recognition and research, new terminology also arises, such as holobiont, which the relationship between a host and its symbionts as one grouping. Many scientists will look at the hologenome, which is the combined genetic information of the host and its symbionts. These terms are more commonly used to describe microbial symbionts.
A bioassay is an analytical method to determine the potency or effect of a substance by its effect on living animals or plants, or on living cells or tissues. A bioassay can be either quantal or quantitative, direct or indirect. If the measured response is binary, the assay is quantal; if not, it is quantitative.