Marine Drug Discovery Research Articles

Targeted metagenomics as a tool to tap into marine natural product diversity for the discovery and production of drug candidates.

Microbial natural products exhibit immense structural diversity and complexity and have captured the attention of researchers for several decades. They have been explored for a wide spectrum of applications, most noteworthy being their prominent role in medicine, and their versatility expands to application as drugs for many diseases. Accessing unexplored environments harboring unique microorganisms is expected to yield novel bioactive metabolites with distinguishing functionalities, which can be supplied to the starved pharmaceutical market. For this purpose the oceans have turned out to be an attractive and productive field. Owing to the enormous biodiversity of marine microorganisms, as well as the growing evidence that many metabolites previously isolated from marine invertebrates and algae are actually produced by their associated bacteria, the interest in marine microorganisms has intensified. Since the majority of the microorganisms are uncultured, metagenomic tools are required to exploit the untapped biochemistry. However, after years of employing metagenomics for marine drug discovery, new drugs are vastly under-represented. While a plethora of natural product biosynthetic genes and clusters are reported, only a minor number of potential therapeutic compounds have resulted through functional metagenomic screening. This review explores specific obstacles that have led to the low success rate. In addition to the typical problems encountered with traditional functional metagenomic-based screens for novel biocatalysts, there are enormous limitations which are particular to drug-like metabolites. We also present how targeted and function-guided strategies, employing modern, and multi-disciplinary approaches have yielded some of the most exciting discoveries attributed to uncultured marine bacteria. These discoveries set the stage for progressing the production of drug candidates from uncultured bacteria for pre-clinical and clinical development.

Signal Transducers and Activators of Transcription (STAT) Regulatory Networks in Marine Organisms: From Physiological Observations towards Marine Drug Discovery.

Part of our ocean’s richness comes from its extensive history of supporting life, resulting in a highly diverse ecological system. To date, over 250,000 species of marine organisms have been identified, but it is speculated that the actual number of marine species exceeds one million, including several hundreds of millions of species of marine microorganisms. Past studies suggest that approximately 70% of all deep-sea microorganisms, gorgonians, and sea sponges produce secondary metabolites with anti-cancer activities. Recently, novel FDA-approved drugs derived from marine sponges have been shown to reduce metastatic breast cancer, malignant lymphoma, and Hodgkin’s disease. Despite the fact that many marine natural products have been shown to possess a good inhibition potential against most of the cancer-related cell signaling pathways, only a few marine natural products have been shown to target JAK/STAT signaling. In the present paper, we describe the JAK/STAT signaling pathways found in marine organisms, before elaborating on the recent advances in the field of STAT inhibition by marine natural products and the potential application in anti-cancer drug discovery.

Can a freshwater aquaculture model be used for marine drug discovery?

Aquaculture ResearchVolume 47, Issue 11 p. 3689-3693 Short Communication Can a freshwater aquaculture model be used for marine drug discovery? João Chambel, Corresponding Author João Chambel [email protected] MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, Portugal Both authors contributed equally for the laboratorial work developed.Correspondence: J Chambel, Polytechnic Institute of Leiria, School of Tourism and Maritime Technology, 2520–641 Peniche, Portugal. E-mail: [email protected]Search for more papers by this authorAndré Horta, André Horta MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, Portugal Both authors contributed equally for the laboratorial work developed.Search for more papers by this authorCelso Alves, Celso Alves MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, PortugalSearch for more papers by this authorSusete Pinteus, Susete Pinteus MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, PortugalSearch for more papers by this authorVera Severiano, Vera Severiano MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, PortugalSearch for more papers by this authorRui Pedrosa, Rui Pedrosa MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, PortugalSearch for more papers by this author João Chambel, Corresponding Author João Chambel [email protected] MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, Portugal Both authors contributed equally for the laboratorial work developed.Correspondence: J Chambel, Polytechnic Institute of Leiria, School of Tourism and Maritime Technology, 2520–641 Peniche, Portugal. E-mail: [email protected]Search for more papers by this authorAndré Horta, André Horta MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, Portugal Both authors contributed equally for the laboratorial work developed.Search for more papers by this authorCelso Alves, Celso Alves MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, PortugalSearch for more papers by this authorSusete Pinteus, Susete Pinteus MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, PortugalSearch for more papers by this authorVera Severiano, Vera Severiano MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, PortugalSearch for more papers by this authorRui Pedrosa, Rui Pedrosa MARE – Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, Peniche, PortugalSearch for more papers by this author First published: 11 May 2015 https://doi.org/10.1111/are.12794Citations: 2 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume47, Issue11November 2016Pages 3689-3693 RelatedInformation

A perspective on toxicology of Conus venom peptides.

The evolutionarily unique and ecologically diverse family Conidae presents fundamental opportunities for marine pharmacology research and drug discovery. The focus of this investigation is to summarize the worldwide distribution of Conus and their species diversity with special reference to the Indian coast. In addition, this study will contribute to understanding the structural properties of conotoxin and therapeutic application of Conus venom peptides. Cone snails can inject a mix of various conotoxins and these venoms are their major weapon for prey capture, and may also have other biological purposes, and some of these conotoxins fatal to humans. Conus venoms contain a remarkable diversity of pharmacologically active small peptides; their targets are an iron channel and receptors in the neuromuscular system. Interspecific divergence is pronounced in venom peptide genes, which is generally attributed to their species specific biotic interactions. There is a notable interspecific divergence observed in venom peptide genes, which can be justified as of biotic interactions that stipulate species peculiar habitat and ecology of cone snails. There are several conopeptides used in clinical trials and one peptide (Ziconotide) has received FDA approval for treatment of pain. This perspective provides a comprehensive overview of the distribution of cone shells and focus on the molecular approach in documenting their taxonomy and diversity with special reference to geographic distribution of Indian cone snails, structure and properties of conopeptide and their pharmacological targets and future directions.

PAVALAM: A VALUABLE SIDDHA MINERAL DRUG

The marine ecosystem is a rich source of drug discovery and development. Pharmacological investigations of marine products ar e providing convincing evidence that marine drug discovery has an exceedingly bright future in health care. The availability of ethno medicinal literature about marine products is very limited. Marine organisms have been used in Siddha system of Medicine since time immemorial. Pavalam (Red coral) i s a valuable mineral drug which is commonly used in day to day practice by Siddha physicians for various ailments. This paper foc uses on its origin, character, purific ation and processing techniques and differe nt form of medicines prepared. The literature review revealed that Pavalam based medicines are widely used for the management of respiratory diseases, bleeding disorders and life style diseases like cancer and diabetes. The various research reports on Pavalam through scientific validation also highlig hted for its future development. The scientific reports confirm the traditional claim of Pavalam’s efficacy.

AN EMERGING MARINE BIOTECHNOLOGY: MARINE DRUG DISCOVERY

Marine natural resources offer an opportunity to discover a novel chemical diversity withinterest ing pharmacologically active compounds to treat many diseases such as cancer,inflammation, bacterial and parasitic infections, and many other diseases. Marine drug discoveryis a rising area in marine biotechnology. Several hits of marine-derived drug compounds wereapproved; two of them are Ziconotide and Trabectedin. In 2004, Ziconotide was approved as paintreatment drugs in the United States and Europe. Then, in 2007, Trabectedin was also approvedas anticancer drug in Europe. The main problem in marine drug discovery research is materialsupply problem. Up till now, strategies to overcome the problem are “Pharmaceutical aquaculture”of biologically active marine biota and chemical synthesis approach. Chemical synthesis approachis feasible solution to be used, especially when working with less complex structure of compounds.However, when working with structurally complex compounds where total or even semi synthesiswas very difficult to be provided, aquaculture can be a solution. Currently, the use of microbiology,biochemistry, genetic, bioinformatics, genomic and meta-genomic has been intensifying in orderto have a better result in marine natural product drug discovery. As chemical synthesis needs anexpensive investment of advanced technology and highly skilled human resources, thuspharmaceutical aquaculture is more practicable to overcome the material supply insufficiency inIndonesia. Up till now, many Indonesian marine bioprospectors have been working with culturablemarine microorganism to produce bioactive compounds and some others starting to work withgenomic and metagenomic-based drug discovery.

Synthesis of an Urea-substituted Selenoisobutyric Acid Isostere of the Peroxisome Proliferator-activated Receptor α Selective Agonist

Center for Marine Natural Products and Drug Discovery, School of Earth and Environmental Sciences, Seoul National University, NS-80, Seoul 151-747, Korea Research Institute of Oceanography, Seoul National University, Seoul 151-741, Korea *E-mail: jwchin97@snu.ac.kr (J. Chin); hjkang@snu.ac.kr (H. Kang) Korea Institute of Science and Technology, Gangneung Institute, Gangneung 210-340, Korea Received August 16, 2011, Accepted September 15, 2011

Cellular Localization of Debromohymenialdisine and Hymenialdisine in the Marine Sponge Axinella sp. Using a Newly Developed Cell Purification Protocol

Sponges (Porifera), as the best known source of bioactive marine natural products in metazoans, play a significant role in marine drug discovery and development. As sessile filter-feeding animals, a considerable portion of the sponge biomass can be made of endosymbiotic and associated microorganisms. Understanding the cellular origin of targeted bioactive compounds from sponges is therefore important not only for providing chemotaxonomic information but also for defining the bioactive production strategy in terms of sponge aquaculture, cell culture, or fermentation of associated bacteria. The two alkaloids debromohymenialdisine (DBH) and hymenialdisine (HD), which are cyclin-dependent kinase inhibitors with pharmacological activities for treating osteoarthritis and Alzheimer's disease, have been isolated from the sponge Axinella sp. In this study, the cellular localization of these two alkaloids was determined through the quantification of these alkaloids in different cell fractions by high-performance liquid chromatography (HPLC). First, using a differential centrifugation method, the dissociated cells were separated into different groups according to their sizes. The two bioactive alkaloids were mainly found in sponge cells obtained from low-speed centrifugation. Further cell purifications were accomplished by a newly developed multi-step protocol. Four enriched cell fractions (C1, C2, C3, and C4) were obtained and subjected to light and transmission electron microscopy, cytochemical staining, and HPLC quantification. Compared to the low concentrations in other cell fractions, DBH and HD accounted for 10.9% and 6.1%, respectively, of dry weight in the C1 fraction. Using the morphological characteristics and cytochemical staining results, cells in the C1 fraction were speculated to be spherulous cells. This result shows that DBH and HD in Axinella sp. are located in sponge cells and mostly stored in spherulous cells.

In vitro antiviral activity against herpes simplex virus in the abalone Haliotis laevigata

As viruses are extremely abundant in oceans, marine organisms may have evolved novel metabolites to protect themselves from viral infection. This research examined a well-known commercial gastropod, abalone (Haliotidae), which in Australia have recently experienced disease due to a neurotropic infection, abalone viral ganglioneuritis, caused by an abalone herpesvirus (AbHV). Due to the lack of molluscan cell lines for culturing AbHV, the antiviral activity of the abalone Haliotis laevigata was assessed against another neurotropic herpesvirus, herpes simplex virus type 1 (HSV-1), using a plaque assay. The concentration range at which abalone extract was used for antiviral testing caused minimal (<10 %) mortality in Vero cells. Haemolymph (20 %, v/v) and lipophilic extract of the digestive gland (3000 μg ml(-1)) both substantially decreased the number and size of plaques. By adding haemolymph or lipophilic extract at different times during the plaque assay, it was shown that haemolymph inhibited viral infection at an early stage. In contrast, the antiviral effect of the lipophilic extract was greatest when added 1 h after infection, suggesting that it may act at an intracellular stage of infection. These results suggest that abalone have at least two antiviral compounds with different modes of action against viral infection, and provide a novel lead for marine antiviral drug discovery.

Photosynthetic marine organisms as a source of anticancer compounds

Since early human history, plants have served as the most important source of medicinal natural products, and even in the “synthetic age” the majority of lead compounds for pharmaceutical development remain of plant origin. In the marine realm, algae and seagrasses were amongst the first organisms investigated by marine natural products scientists on their quest for novel pharmaceutical compounds. Forty years after the pioneering work in the field of marine drug discovery began, the biodiversity of marine organisms investigated as potential sources of anticancer, anti-inflammatory, and antibiotic compounds has increased tremendously. Nonetheless, marine plants are still an important source of novel secondary metabolites with interesting biomedical properties. The present review focuses on the antitumour properties of compounds isolated from marine algae, phytoplankton, mangroves, seagrasses, or cordgrasses. Compounds produced by marine epi- or endophytic fungi are also discussed.

Isolation and biological activity of ( E)-1-(4-hydroxystyryl)guanidine from the sub-Arctic ascidian, Dendrodoa aggregata

Isolation and biological activity of (E)-1-(4-hydroxystyryl)guanidine from the sub-Arctic ascidian, Dendrodoa aggregata Margey Tadesse *, Veronika Torfoss , Morten B. Strom, Espen Hansen , Jeanette Hammer Andersen , Klara Stensvag , Tor Haug a,d Department of Marine Biotechnology, The Norwegian College of Fishery Science, University of Tromso, Breivika, N-9037 Tromso, Norway Department of Pharmacy, Faculty of Medicine, University of Tromso, Breivika, N-9037 Tromso, Norway MARBIO, University of Tromso, Breivika, N-9037 Tromso, Norway Centre for Research-based Innovation on Marine Bioactivities and Drug Discovery (MabCent), University of Tromso, Breivika, N-9037 Tromso, Norway

Correction: Hong, K. et al. Actinomycetes for Marine Drug Discovery Isolated from Mangrove Soils and Plants in China. Mar. Drugs 2009, 7, 24–44

We found an error in our paper published in Marine Drugs [1]. [...]

Actinomycetes for marine drug discovery isolated from mangrove soils and plants in China.

The mangrove ecosystem is a largely unexplored source for actinomycetes with the potential to produce biologically active secondary metabolites. Consequently, we set out to isolate, characterize and screen actinomycetes from soil and plant material collected from eight mangrove sites in China. Over 2,000 actinomycetes were isolated and of these approximately 20%, 5%, and 10% inhibited the growth of Human Colon Tumor 116 cells, Candida albicans and Staphylococcus aureus, respectively, while 3% inhibited protein tyrosine phosphatase 1B (PTP1B), a protein related to diabetes. In addition, nine isolates inhibited aurora kinase A, an anti-cancer related protein, and three inhibited caspase 3, a protein related to neurodegenerative diseases. Representative bioactive isolates were characterized using genotypic and phenotypic procedures and classified to thirteen genera, notably to the genera Micromonospora and Streptomyces. Actinomycetes showing cytotoxic activity were assigned to seven genera whereas only Micromonospora and Streptomyces strains showed anti-PTP1B activity. We conclude that actinomycetes isolated from mangrove habitats are a potentially rich source for the discovery of anti-infection and anti-tumor compounds, and of agents for treating neurodegenerative diseases and diabetes.

Drugs from the Sea - Opportunities and Obstacles

The supply problem with regard to drug development and sustainable production lies in the limited amounts of biomass of most marine invertebrates available from wild stocks. Thus, most pharmacologically active marine natural products can only be isolated in minute yields. Total synthesis of pharmacologically active natural products has been successfully established but is in many cases economically not feasible due to the complexity of the molecular structures and the low yields. To solve the pressing supply issue in marine drug discovery, other strategies appear to be more promising. One of these is mariculture which has successfully been established with the bryozoan Bugula neritina (the source of the bryostatins) and the tunicate Ecteinascidia turbinata (the source of ET-743). Another strategy involves partial synthesis from precursors which are biotechnologically available. An example is ET-743 that can be partially synthesized from safracin B which is a metabolite of Pseudomonas fluorescens. There have been many examples of striking structural similarities between natural products obtained from marine invertebrates and those of microbial origin which suggests that microorganisms living in their invertebrate hosts could be the actual producers of these secondary metabolites. With regard to sustainable biotechnological production of pharmacologically important metabolites from marine invertebrates and their “endosymbionts”, a more advanced strategy is to focus on cloning and expression of the respective key biosynthetic gene clusters. This molecular biological approach will open up new avenues for biotechnological production of drugs or drug candidates from the sea.

New pharmaceuticals from marine organisms

Definitions of 'marine biotechnology' often refer to the vast potential of the oceans to lead to new cures for human and animal disease; the exploitation of natural drugs has always been the most basic form of biotechnology. Although only initiated in the late 1970s, natural drug discovery from the world's oceans has been accelerated by the chemical uniqueness of marine organisms and by the need to develop drugs for contemporary, difficult to cure, diseases. Current research activities, while primarily within the academic laboratories, have generated convincing evidence that marine drug discovery has an exceedingly bright future.

Sea Grant seeks new drugs from the sea

After more than 20 years of leadership in the field of marine drug discovery, Sea Grant researchers are now demonstrating that marine organisms are an excellent source of new drugs. New treatments have been discovered for arthritis and cancer, and novel molecular probes have been commercialized that allow studies of previously unknown cellular processes. Through patenting and licensing, UC has begun to receive significant royalties for these discoveries. As this field matures, it has become clear that the world's oceans contain an enormous wealth of medical information that will continue to contribute to the discovery of new cures for human disease.