Past: Early discoveries in marine pharmaceuticals
Present: Marine pharmaceuticals in modern medicine
Future: Innovations and potential in marine pharmaceuticals
Commercial relevance
Conclusion
The ocean covers more than 70% of the Earth’s surface and consists of a vast reservoir of bioactive compounds. Additionally, more than 80% of the world’s species, as well as a high volume of microorganisms, can also be found in the oceans due to the diverse conditions of the marine environment.1
The temperature of the oceans can range from -1.5 degrees Celsius in the frozen seas of both poles to 350 degrees Celsius in the hydrothermal ecosystems on the ocean floor. This can lead to the high level of biodiversity found in the oceans, which also reflects its high level of chemodiversity.1
The rich compounds found in the oceans comprise significant pharmaceutical potential, with marine-derived compounds contributing to drug development for various diseases and disorders, including cancer, infections, and inflammatory conditions such as hypertriglyceridemia, which involves inflammation of the pancreas.1,2
Image Credit: Alina Kruk/Shutterstock.com
Past: Early discoveries in marine pharmaceuticals
Interestingly, while plant-based medicines have been historically used for over 5,000 years and microbially-derived medicines have been used for nearly a century, bioactive compounds from marine sources have only been investigated and used in pharmaceuticals relatively recently. This may be due to funding from the US National Cancer Institute in the 1960s, which led to more than 15-20 marine-derived pharmaceutical products related to cancer treatment receiving clinical approval as potential medicine.3
Additionally, early funding in the 1940s from the US National Institute of Health in basic studies on sponge metabolites resulted in finding what is considered to be the first marine bioactive agent, which led to drugs that were used in humans.3
Groups of marine investigators that received funding from the National Cancer Institute also worked on plants and aquatic invertebrates, which led to the development of drug candidates.3
The development of a marine-derived drug for anti-cancer therapeutics evolved through the discovery of cytarabine in the early 1950s, found within Cryptotethia crypta, a species of sponge.
Cytarabine was discovered as a nucleoside containing arabinose sugar. It is an anti-metabolite and anti-neoplastic agent that belongs to the anthracycline category of drugs, with indications for the treatment of (i) acute lymphoblastic leukemia, (ii) remission induction therapy in acute myeloid leukemia, as well as (iii) the prophylaxis and treatment of meningeal leukemia.4
A notable marine-derived drug for non-oncology indications included ziconotide, which was granted Food and Drug Administration (FDA) approval in 2006 for the treatment of chronic pain.
It was also used as a primary alternative to morphine due to its powerful analgesic properties, including having up to 1,000 times higher analgesic potency than a calcium ion channel blocker. However, a challenge for this pharmaceutical is its requirement for a complex method of delivery into the spine, which is an obstacle that has limited its use.3
Key FDA Decisions Made in 2024
Present: Marine pharmaceuticals in modern medicine
Advancements in research
The development of biotechnology has spearheaded many fields, including the use of high-throughput molecular methods such as High Throughput Sequencing (HTS).5
HTS has had a great impact on the discovery of marine-derived compounds due to its capacity to be directly used on intact seawater samples without the need to be isolated previously or require the cultivation of individual microorganisms. Rather, HTS utilizes specific gene regions or barcodes to provide a significant volume of genetic data on a range of microbial communities, with ongoing improvements in areas such as quality of data, bioinformatic analysis strategies, and read length, which result in reflecting a better representation of the genetic-based taxonomic diversity within the sample.5
Additionally, advancements in omics technologies, including increased sensitivity and specificity through next-generation HTS combined with liquid chromatography-mass spectrometry and nuclear magnetic resonance, are also accelerating the discovery of bioactive compounds.6
Current applications
Many marine-derived drugs are currently in use or being tested through clinical trials. An example includes eribulin, which is a synthetic macrocyclic ketone analog of halicondrin B, known to be a high molecular weight compound that was isolated in 1986 from the Halichondria okadai sponge from Japan. This compound was found to show significant inhibition of cell growth in many human cancer cell lines. It was granted FDA approval as an anti-neoplastic medical product called Halaven® in 2010 in the USA and 2011 in Europe.1
Eribulin was approved for two indications: (i) the treatment of adult patients with locally advanced and metastatic breast cancer with disease progression after at least one chemotherapy treatment, including the use of an anthracycline and a taxane; (ii) the treatment of adult patients with inoperable liposarcoma after receiving anthracycline-containing therapy for advanced or metastatic disease. The approval of the second indication came in 2016 by both the FDA and the European Medicines Agency (EMA).1
An example of a successful marine-derived drug in clinical trials includes bryostatin, which is a macrocyclic polyketide lactone sourced from the bryozoan Bugula neritina, and works by acting as a potent modulator of the protein kinase C.
This marine-derived drug is being tested within clinical trials for its use as an anti-cancer therapeutic, an anti-AIDs/HIV agent, and for treating neurodegenerative Alzheimer’s disease.3
Challenges
While there are challenges with using marine sources for drug compounds, including a sustainable strategy to collect and obtain the required supply, there may be an approach to overcome this.3
An example of an innovative solution for maintaining the supply of bryostatin included an interesting strategy involving its producer, bryozoan, which was successfully grown using in-sea and on-land aquaculture, resulting in a high enough level of bryostatin to obtain the required supply.3
Suppose the supply of marine organisms and bioactive compounds can be solved economically and ecologically. In that case, there may be a higher probability of marine-derived drugs being made available on the market. With sustainability in mind, if a collection of bioactive compounds cannot be sustainable, marine biotechnology processes such as aquaculture or mariculture, for example, may be able to solve these problems.7
Additionally, while total synthesis is possible by principle for several known marine compounds, it may only be economically feasible for simple products such as ziconotide.7
Marine Natural Products: From Sea to Pharmacy
Future: Innovations and potential in marine pharmaceuticals
Emerging technologies
In order to solve the challenge of sustainable supply of various marine-derived products, with total synthesis being less feasible, another alternative may involve semi-synthetic production. This consists of easily available compounds that are transferred by chemical or biochemical processes into a finalized product.7
In many cases, it is not always necessary to produce the whole structure of an original natural compound, even when it’s the lead structure. The use of chemical or enzymatic alterations of a natural compound as a lead structure can have many benefits, including higher structural variability and improved other properties of the product.7
Another emerging technology that may have a role in unlocking marine-derived drug potential includes artificial intelligence (AI), with many scientists being able to use the tool to predict how the chemical structure of a natural product can impact its activity as well as which macromolecule may be its biological target.
An example of the use of AI in drug discovery included the use of AlphaFold, a deep learning system, to predict the 3D structure of proteins from their primary amino acid sequence.3
Unexplored ecosystems
While biodiversity hotspots have been found around the globe, the deep seas have not been fully investigated, resulting in a lack of discovery of its pharmaceutical potential.3
Many invertebrates in these deep-sea environments have no apparent physical defenses and do not have an immune system; however, some filter-feeding invertebrates have developed a chemical defense strategy, which can act as an alternative immune system.3
Interestingly, natural products produced as part of this chemical defense system can have similar characteristics to drug molecules. The screening of marine invertebrates led to the finding that particular phyla had a higher occurrence of bioactivity against human disease screens compared to terrestrial natural products.3
The potential of the deep sea may be monumental; however, without further exploration of oceans and extreme marine environments, potentially revolutionary marine-derived bioactive molecules may be left untouched and undiscovered.3
Sustainability and bioprospecting
Sustainable harvesting strategies, as previously mentioned, include aquaculture and cultivation, which is established for the reproduction marine animals such as fish and some mussels for food purposes and macroalgae.7
Aquaculture consists of the controlled cultivation of aquatic organisms in the sea or within artificial environments, which has been evidenced to be a valid option for large-scale production in many instances.
However, a detailed understanding of the living conditions in the natural environment is required for optimal cultivation. This is also the case for microorganisms for microbial fermentation or the co-cultivation of two or more different strains, known as mixed fermentation.3
Placebos: An Overview
Commercial relevance
Industry growth
Marine biotechnology comprises a niche field within larger ocean-based industries; however, it has become a growing area of research with a projection that in 2030, ocean-based sectors will outperform the growth of the global economy, with an estimated 40 million full-time or equivalent jobs.5
With marine-derived compounds being an innovative and obscure source of novel drug candidates for many diseases, it is no surprise that the global market for marine-derived pharmaceuticals has been predicted to grow from USD 2,922.11 million in 2023 to USD 5,341.16 million by 2030, with a compound annual growth rate (CAGR) of 9%.8
Market opportunities
The market opportunities for marine-derived compounds are significant, with a high demand for anti-cancer drugs, antibiotics, and anti-inflammatory agents. Additionally, with the emergence of antibiotic-resistant bacteria and, in turn, resistant infections, the use of these substances may be revolutionary for medicine and patient health worldwide.8
Collaborative efforts
The US National Institute of Health and the National Institute of Cancer have been two significant groups that have pioneered the search for marine-derived bioactive agents due to funding research in these areas.3
Since then, others have also continued this work, with more than 20 compounds in clinical trials and more than 300 patents that have been accepted. Additionally, many bioactive new chemical entities (NCEs) with anti-cancer properties have also been patented and spearheaded by university institutes around the globe, with innovative solutions for sourcing these products sustainably.9
Conclusion
Marine sources have had a transformative role in drug discovery, with its potential not being fully realized due to the large masses of deep oceans and extreme conditions being left untouched. However, the promise of its pharmaceutical potential has been enough to excite researchers who are aiming for a breakthrough to find potent drug candidates for a range of diseases.3
However, consideration is still required for sustainable and innovative approaches when sourcing these natural materials to ensure a high enough supply to meet the global demand. At the same time, further exploration of the ocean’s pharmaceutical potential continues forward.3,7
References
- Cappello E, Nieri P. From life in the sea to the clinic: The Marine Drugs approved and under clinical trial. Life. 2021;11(12):1390. doi:10.3390/life11121390.
- Hypertriglyceridemia: Causes, risk factors & treatment. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/23942-hypertriglyceridemia. Published May 1, 2024. Accessed December 4, 2024.
- Francesch AM, Glaser KB, Jaspars M, et al. Pharmaceuticals from marine sources: Past, present and future. Pharmaceutical Journal. 2024;313(7987). doi:10.1211/pj.2024.1.324083.
- Faruqi A. Cytarabine. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK557680/. Published August 8, 2023. Accessed December 4, 2024.
- Rotter A, Barbier M, Bertoni F, et al. The Essentials of Marine Biotechnology. Frontiers in Marine Science. 2021;8. doi:10.3389/fmars.2021.629629.
- Rosic NN. Recent advances in the discovery of novel marine natural products and mycosporine-like amino acid UV-absorbing compounds. Applied Microbiology and Biotechnology. 2021;105(19):7053-7067. doi:10.1007/s00253-021-11467-9.
- Lindequist U. Marine-derived pharmaceuticals - challenges and opportunities. Biomolecules & Therapeutics. 2016;24(6):561-571. doi:10.4062/biomolther.2016.181.
- Marine-derived pharmaceuticals market by type (phenol, steroid, ether, peptide, mollusk, sponge, tunicate, others) source (algae, invertebrates, microorganisms) mode of delivery (anti-microbial, anti-tumor, anti-cardiovascular, anti-viral, anti-inflammatory, others) end user (hospitals, retail pharmacy, online pharmacy, others) and region, global trends and forecast from 2023 to 2030. Exactitude Consultancy. https://exactitudeconsultancy.com/reports/32945/marine-derived-pharmaceuticals-market/. Published June 18, 2024. Accessed December 4, 2024.
- Saeed AFUH, Su J, Ouyang S. Marine-derived drugs: Recent advances in cancer therapy and immune signaling. Biomedicine & Pharmacotherapy. 2021;134:111091. doi:10.1016/j.biopha.2020.111091.
Further Reading