Coral reef biomedicine and pharmacology in review: marine

ecosystems rich in diverse metabolites

A.R. Papariello
Rosenstiel School of Marine and Atmospheric Science, University of Miami, 4600 Rickenbacker
Causeway, Miami, Florida 33149, USA

Abstract
Coral reefs are a host to a wide variety of unique, bioactive compounds that have developed out
of evolutionary necessity during complex organism and environment interactions. The huge
array of biologically active metabolites found in coral reef ecosystems make these marine
environments natural pharmacies which serve as an excellent starting point for drug discovery
and novel biomedical research. Marine biomedicine is a small yet growing field of scientists who
focus on discovering and utilizing these novel compounds in an attempt to benefit human health
and research. Important sources of active metabolites in coral reef ecosystems include
cyanobacteria, sponges, cnidarian, bryozoans, and tunicates. Once isolated from their organism,
these compounds can have a variety of medically relevant functions and may show antibacterial,
antiviral, and anti-inflammatory properties in-vivo and in-vitro. In addition to this, the
compounds mechanism of action may be completely unique and can potentially serve as a
platform for new research directions. Ultimately, the goal of marine biomedicine and
pharmacology is to have marine derived compounds pass clinical trials and become FDA
approved pharmaceuticals.
Key words: Marine biomedicine Coral reef chemodiversity Anti-microbial compounds
Anti-viral and anti-HIV treatments Marine derived analgesics Drug discovery

Introduction
Coral reefs are some of the most diverse ecosystems on planet and support extremely productive
and complex organism interactions. They are built by small invertebrate Anthozoa polyps that
secrete calcium carbonate or silicate exoskeletons which acts as the framework of the reef
(Levinson 2009). It is this slow process that creates entire reef systems that may be thousands
upon thousands of years old. Often times these individual coral polyps host symbiotic
dinoflagellate algae called zooxanthellae that are unicellular and provide the polyp with oxygen
and nutrient products via photosynthesis (Rosenberg et al. 2007). Coral reefs are often found in
warm, coastal, tropical and subtropical regions extending from the northern 25th latitude to the
southern 25th latitude (Levinson 2009). The largest and most diverse coral reefs are found in the
Indo-Pacific region around South East Asia and the Philippines (Levinson 2009). Other areas that
have significantly large areas of coral reefs include Australia which hosts the 2600 kilometer
long Great Barrier Reef and the Caribbean.
Coral reefs are centers of biodiversity and complex organism competition and interaction.
Their structure provides protection for smaller fish and sessile organisms while hosting a hotspot
of food for larger predators. Sponges, mollusks, crustaceans, echinoderms, and marine worms all

call the reef home and are some of the most common inhabitants in these ecosystems. A wide
variety of bacteria and viruses also call coral reefs home and because of this, the immune
systems of many organisms are distinctively developed (Rosenberg at al. 2007). Some organisms
such as fish and crustaceans have incorporated marine microbes into their digestive systems
creating a mini-ecosystem of chemical interactions within the host organism (Rosenberg et al.
2007). The complexity of organism interactions in an extremely biodiverse environment, even at
a cellular-molecular level, provides the foundation of metabolite diversity within marine
organisms and habitats (Montaser and Luesch 2011). The intricacy of cellular interactions within
coral reef communities leads to a special kind of evolutionary adaption where unique bioactive
molecules called secondary metabolic compounds are developed for a wide range of reasons by a
host organism. The more diverse a habitat is, the more unique the chemicals are that are
produced. Occasionally, not only are the chemicals unique, but the mechanisms of action they
use are as well (Montaser and Luesch 2011). It is presumed that the high levels of biodiversity in
coral reef habitats is the primary cause of chemical diversity and it is this factor that makes coral
reefs an excellent focal point of novel molecular and pharmaceutical research (Montaser and
Luesch 2011).
Marine biomedicine is a relatively small multidisciplinary field of study that focuses on
this multifaceted relationship between marine organisms and their environment using a wide
array of biologic and chemical analysis techniques. Often time there is an emphasis on human
health in the research with goals directed towards drug discovery and development. Current preclinical and clinical research focuses a majority of their attention on anti-cancer compounds but
antimicrobial and anti-inflammatory compounds also have a good amount of literature. This field
sees the oceans as a natural pharmacy and seeks to explore the wide array of unique chemicals
produced in marine environments (Dias et al. 2012). Another objective of marine biomedicine
besides drug development is to better understand humanitys evolution, physiology, and niche
through the use of model organisms. One example of this kind of study is the research of urea
transporters in euryhaline elasmobranchs to better understand human kidney physiology and
possibly develop new drugs aimed at dialysis patients or people who suffer kidney failure
(McDonald et al. 2006). The use of nature as a source of therapeutics is certainly not a new or
revolutionary idea. The Egyptian pharmaceutical record The Ebers Papyrus is a nearly five
thousand year old document that features a list of over 700 plant-derived pills, ointments, and
washes that can treat a wide variety of ails (Dias et al. 2012). Common pharmaceuticals are often
derived from natural sources and approximately half of the top 20 leading best-selling
pharmaceuticals have their origin in natural compounds (Montaser and Luesch 2011).

Marine derived natural products from coral reef ecosystems

Antimicrobial compounds
Living in an ecosystem that has astoundingly high biodiversity can lead to bacterial susceptibility
due to the unique adaptations bacteria develop in environments of fluctuating conditions and
high predation. Coral reefs provide scientists with a hot bed of antimicrobial compounds utilized
by microscopic bacteria and algae, invertebrates such a Porifera and Cniaria, and even in the
chordata Ascidia. The development and pursue of novel antibiotic compounds and fungicides is
an important sector of drug development in todays world. Drug-resistant bacteria such as MRSA

a.

b.

Fig 1. Source organisms of marine derived antimicrobial and antifungal compounds. a. The Indian sponge
Clathria indica which has activity against drug resistant Salmonella and C. albicans. b. The sea squirt
Styela clava which is a source of antimicrobial clavanins and styelin A and B.

can be found in hospitals where microorganisms have evolved immunity to antibiotics at an

increasingly alarming rate; it seems as if the rate of novel antibiotic production cannot keep up
with bacterial replication and evolution. This facet of medicine highlights the importance of the
ocean as a source for ulterior pharmacologic treatments when terrestrial based treatments fail.
Starting small, antibacterial activity can be found in a seemingly unlikely place: marine
bacteria. The antibiotic benzo[]naphthacene quinone arenimycin can be found in the obligate
marine actinomycete Salinispora arenicola (Subramani and Aalbersberg 2012). Arenimycin has
been shown to have effective activity against some strains of antibiotic-resistant Staphylococcus
aureus and powerful antimicrobial effect against a handful of Gram-positive pathogens including
drug-resistant Staphylococci (Subramani and Aalbersberg 2012). Lantipeptides are compounds
produced by marine cyanobacteria that show some antimicrobial activity (Kehr et al. 2011).
Marine algae have been assessed rigorously for antimicrobial action and are known to produce
terpenoid-type structures that show promise as antibacterial and antifungals (Dias et al 2012).
Crenuladial, a diterpenoid secondary metabolite of the marine brown algae Dilophus ligulatus,
has significant antibiotic properties against the bacterium Aeromonas hydrophila,
Staphylococcus aureus, and Micrococcus luteus (Tringali et al. 1988).
Marine sponges have been studied as hosts of antibacterial and antifungal compounds and
show promise in future research of antimicrobial alkaloids. Sponge derived antimicrobial
metabolic peptides are a major constituent of their invertebrate innate immune defensive
mechanisms and likely had origins in endosymbiotic bacteria (Ravichandran et al. 2011). A
screening of sponge derived antibiotic compounds was done in 1969 by Burkholder and Ruetzler
which showed over half of the 31 sponges tested had some kind of gram-positive or gramnegative antibacterial effect. The Indian sponge Clathria indica was fractionated and tested
against various bacteria and funguses by Ravichandran et al; it showed antibacterial activity
against drug resistant Salmonella typhi as well as antifungal activity against C. albicans and C.
neoformans (2011). The Australian sponge genuses Axinella and Oceanapia have been important
hosts to the isolated antibacterial alkaloids axinellamines B-D and petrosamine B, respectively

(Laport et al 2009). Axinellamine B-D and petrosamine B was shown to have a strong
bactericidal activity against the Gram-negative bacterium Helicobacter pylori by inhibiting the
enzyme aspartyl semialdehyde dehydrogenase; this is an important discovery since the H. pylori
bacteria is often associated with peptic ulcers and gastric cancer (Laport et al 2009). Antifungals
have also been isolated from sponges although they are less numerous and less diverse; this is
likely due to their cytotoxic effects (Laport et al. 2009). Lasonolide A, a polyketide isolated from
the sponge Forcepia sp, and manzamine alkaloids isolated from the Acanthostrongylophora sp,
are two sponge derived antifungals currently in preclinical study that show promise for further
development in the pharmaceutical pipeline (Laport et al. 2009).
In addition to sponges, corals also contribute to novel antimicrobial research through
their innate immune system. One possible method of dealing with harmful or overabundant
bacteria is through the surface accommodation of beneficial bacteria and mucus that may
compete with pathogens and release antibacterial chemicals (Geffen et al 2009). In Jensen et als
1996 study, 15 strains of marine bacteria were exposed to 39 Caribbean gorgonian species and
the corals were evaluated for antimicrobial activity. The Pseudopterogorgia sp showed the
highest amount of activity by inhibiting in between 43 and 86% of the bacterial strains but did so
with variable potency (Jensen et al. 1996). Scleractinian corals that undergo mechanical stress
similar to predatory bite appear to have better antibacterial activity than gorgonians and showed
both Gram-positive and Gram-negative efficacy (Geffen and Rosenberg 2005).
The ascidian Styela clava has been the focus of some research due to the antimicrobial
activity of the clavanin peptide family. Synthetically created clavanin A displayed activity
against the common human pathogens Escherichia coli, Listeria monocytogenes, and Candida
albicans and its mechanisms of action appeared to target and disrupt bacterial membranes by
generating transmembrane electrical gradients (Tincu and Taylor 2004). In addition to the
clavanins, S. clava produces the antimicrobial pepties styelin A and B; these peptides were
effective against both Gram-positive and Gram-negative bacteria (Tincu and Taylor 2004).
Crustaceans produce a variety of antimicrobial compounds that are utilized in their
hemolymph to eliminate pathogens and the most prominent and well researched peptides are the
penaeidins (Tincu and Taylor 2004). The penaeidines are small, cationic, amphiphatic peptides
that show potent antibacterial and antifungal activity on a wide range of microorganisms (Tincu
and Taylor 2004). Isolated penaeidines from P. vannamei hemolymph have broad-spectrum
filamentous fungicidal activity and moderately specific antibacterial characteristics; these
peptides appear to be more active against Gram-positive bacteria and utilize bacteriostatic
strain-specific inhibition mechanisms (Tincu and Taylor 2004). Production of antifungal
penaeidines correlates with hemocyanin proteolysis, thus it is possible respiratory pigments
function as part of the shrimp immune system (Tincu and Taylor 2004). Antimicrobial activity
has been observed in the hemolymph of a wide variety of reef dwelling crustaceans including the
hermit crab and the king crab (Tincu and Taylor 2004).
HIV treatments and anti-viral compounds
Coral reefs and the organisms that inhabit them are a significant source of novel anti-viral and
anti-retroviral treatments. The field of anti-viral drug discovery is an important and growing one;
there has been much advancement over the past ten years that has led to the idea that viral
replication can be stopped in a similar manner to bacterial growth. There are currently two FDA
approved pharmaceuticals, vidarabine and azidothymidine, with origins in marine compounds

that exhibit anti-viral or anti-retroviral effects. The first drug, vidarabine, is a synthetic purine
nucleoside derivative developed as an anti-viral for life threatening cases of the human herpes
simplex virus infection (Whitley et al. 1980). The compound has its origin in the isolated
nucleoside spongouridine found in the Caribbean demosponge Tethya crypta and its mode of
action relies on the inhibition of viral DNA polymerase which halts DNA synthesis of the herpes
virus (Meyer et al. 2010). The second FDA approved drug is azidothymidine or AZT which can
be considered a marine derivative of a Porifera compound even though it has been altered
significantly during its development. Azidothymidine is a thymidine analogue that, like
vidarabine, is derived from the purine nucleoside spongouridine found in various tropical
Porifera species (Newman and Cragg 2004). Its efficacy as an HIV treatment is based on a
biochemical mechanism that inhibits reverse transcriptase and terminates DNA-chain
elongation (Fischl et al. 1987).
In addition to these FDA approved compounds there are also numerous other spongederived antiviral compounds in preclinical research. Avarol is hydroquinone derived from the
sponge Dysidea avara and has a relatively well understood mechanism of HIV inhibition; the
compound almost completely [blocks] the synthesis of the natural UAG suppressor glutamine
transfer tRNA which is crucial for the synthesis of a viral protease central to HIV proliferation
(Sipkema et al 2005). Hydroxy derivatives at the 6 and 3 position of avarol also showed a
potent inhibition effect on HIV reverse transcriptase which plays a central role in early HIV
infection and propagation by converting viral genomic RNA into proviral double-stranded
DNA and thus enabling the integration of viral DNA into host DNA (Sipkema et al. 2005)
Papuamides C and D are novel cyclic depsipeptides with anti-viral activity first isolated in the
reef dwelling, Pacific sponges Theonella mirabilis and Theonella swinhoei (Ford et al. 1999).
Despite initial research showing promise as an anti-viral, their mechanism of viral inhibition
remains poorly understood and characterized. Generally marine derived anti-viral compounds
have been predominantly derived from sponges and based on the treatment of an infected patient
as opposed to viral protection or immunity (Sipkema et al. 2005). Many anti-virals of sponge
origin, such as the Xestospongia sp. derived sulfated sterol haplosamates A and B, have
mechanisms that remain a mystery despite initial research showing promise.
Marine microbes have been studied much less voraciously than reef-dwelling sponges in
the field of drug discovery but have produced some potential in anti-HIV pharmaceuticals. The
Alteromonas genus of bacteria was isolated from the tissue of a Bermuda sponge and shown to
produce a metabolic metabolite that has potential as a reverse transcriptase inhibitor (Jha and Zirong 2004). Extracts of the cyanobacterium Lyngbya lagerhaimanii and Phormidium tenue have
shown some usefulness as anti-HIV compounds (Jha and Zi-rong 2004).
A handful of reef-dwelling species of mollusks, tunicates, and echinoderms produce
active secondary metabolites that have some activity against viruses and HIV. The sea hare
Bursatella leachii releases the active anti-HIV protein Bursatellanin-P in its purple ink; the
effectiveness of this compound as an anti-HIV treatment was determined after purification of the
ink and further isolation (Jha and Zi-rong 2004). The tunicate Eudistoma produce the anti-viral
peptides eudistomins and these have been shown to be potent inhibitors of viral activity (Jha and
Zi-rong 2004). Ten novel saponins isolated from the starfish Certonardoa semiregularis were
evaluated for antiviral activity against a wide range of viruses that affect humans including HIV,
Coxsachie, herpes simplex, encephalomyocarditis virus, and vesicular stomatitis virus but there
was only mild potency observed for two of the saponins (Jha and Zi-rong 2004).

Anti-inflammatory and analgesic compounds

Anti-inflammatories are some of the most commonly used prescribed and over the counter
medications in the Unites States and treat a wide range of every day and chronic symptoms.
While inflammation is a normal part of the bodys biological response to harmful stimuli and is
crucial to fighting infection, over stimulation of the inflammatory response is linked to chronic
disease and poor health (Senthilkumar and Kim 2010). Much of the novel drug research that is
focused on anti-inflammatories today is looking to alleviate the gastrointestinal side effects and
harsh impact on the liver caused by chronic use of current drug treatments (Pearce et al 2007).
Drug discovery in marine environments is not the only focus of research; the elucidation of the
cellular signaling cascades and mechanisms within the inflammatory pathway also has an
important role in current research. There are a handful of sponges, corals, and sea squirts that
have shown anti-inflammatory activity and their mechanism of action has been successfully
determined for the most part.
Three bioactive alkaloids have been isolated and characterized from two sponge species
and one ascidian species. The New Zealand ascidian Aplidium sp. contains two novel alkaloids,
ascidiathiazones A and B, which are 2-quinolinequinone carboxylic acid derivatives (Pearce et al
2007). These alkaloids inhibited superoxide production in human neutrophils in vitro and show
potential in the advancement of anti-inflammatory treatments. The sponge Stylissa carteri
produces the alkaloid cateramine A which, like the ascidiathiazones, works on inhibiting
neutrophil chemotaxis to produce anti-inflammatory effects (Senthikumar and Kim 2010). The
alkaloid cateramine A is unique in its structure-function relationship and is seen as a novel
platform for drug discovery in inflammatory based research. Manzamine is an alkaloid found in
various sponge species and was found to be a potent inhibitor of thromboxane generation
(Senthikumar and Kim 2010). Thromboxane generation from arachidonic acid derivatives is an
important step in the inflammatory pathway and its inhibition is an important factor that leads to
a decreased inflammation response.
Non-alkaloid chemicals such as cembranolides and durumolides are compounds that
exhibit anti-inflammatory effect and are found in the soft coral genus Lobophytum (Senthikumar
and Kim 2010). Both of these compounds had isolated derivatives that exhibited significant
effect by inhibiting COX-2 (cyclooxygenase) enzyme synthesis of inflammatory prostaglandins
in vitro (Senthikumar and Kim 2010). The sponge P. angulospiculatus produces the polyketide
Plakortide P which has been characterized as a potent inhibitor of thromboxane B2 release in rat
microglia thus making it a novel antineuroinflammatory agent (Senthikumar and Kim 2010).
Manoalide, a sesterterpenoid, is perhaps one of earliest isolated and best described
sponge derived compounds and has been shown to have both anti-inflammatory and analgesic
effects (Sipkema et al 2005). The compounds anti-inflammatory mechanism relies on stopping
the release of arachidonic acid from membrane anchored phosopholipids via irreversible
inhibition caused by the prevention of phospholipase A2 from attaching to the membrane
(Sipkema et al 2005). Inflammatory mediators such as prostaglandins and leukotrienes are
upregulated as a result of the increasing intracellular arachidonic acid concentration and
inflammation is eventually lessened (Sipkema et al 2005). This unique method decreasing
inflammation via phospholipase A2 inhibition is found only in a few sponge-derived
sesterterpenes and has spawned hundreds of chemical analogues with some compounds even
making it into clinical trials (Sipkema et al 2005).

Analgesics are an important class of drugs that provide pain relief and along with antiinflammatories, are some of the most widely used drugs in the United States. Current direction in
analgesic drug development is slowly pushing towards the creation of compounds that can
relieve chronic and severe pain with little abuse or addiction potential. The most notable
analgesic compound of marine origin that follows this model is the FDA approved atypical
analgesic ziconotide which is now a treatment option for patients with severe, chronic pain who
are intolerant to other first line treatments (Proksch 2002). Ziconotide is a 25 amino-acid linear
peptide synthetically equivalent to the compound -conotoxin MVIIA which is found in the
potentially deadly venom of the predatory Indo-Pacific mollusc Conus magus (Proksch 2002). Its
mechanism of action and subsequent analgesic effects are a result of a very potent and highly
selective blockade of mammalian neuronal N-type voltage-sensitive calcium channels (NVSCCs) (Miljanich 2004). N-VSCCs mediate nearly all calcium-dependent neurotransmitter
release at neuronal synapses within the nervous system and are thus are an important factor in the
perception, detection, and transmission of pain (Miljanich 2004). Ziconotide stops the neuronal
transmission of noxious stimuli traveling from the nociceptors to the brain by selectively
blocking the N-VSCCs located at the primary nociceptors central terminal, thus halting neuronal
transmission of pain in route to the brain via spinal interneurons (Miljanich 2004). In addition to
its highly unusual mechanism of action, ziconotide has been characterized to be more pain
relieving than morphine in animal models and shows no tolerance, unlike its opioid counterparts
(Proksch 2002).

Mechanism of
Compound

Organism of origin
actiom
Inhibits superoxide production

Ascidiathiazones A and B

Ascidian, Aplidium sp
in neutrophils

Cateramine A

Porifera, Stylissa carteri

Inhibits neutrophil chemotaxis

Inhibits thromboxane B2

Plakortide P

Porifera, P. angulospiculatus
release

Cembranolides and
Anthozoa, Lobophytum sp

Inhibiting COX-2 enzyme

Durumolide
Irreversible inhibition of
Manoalide

Porifera, Luffariella sp.

arachidonic acid
N-type voltage-sensitive

Ziconotide

Mollusca, Conus magus

calcium channels blockage

Table 1. Quick summary of some anti-inflammatories and analgesics

Cardiovascular and psychiatric treatment exploration

Due to the focus on novel cancer treatments, other chronic illnesses such as heart disease,
diabetes, and arthritis often get overlooked in the marine pharmaceutical pipeline. While the
research on marine derived compounds as treatment options for these conditions is scant
compared to cancer and antimicrobial research, it is worth highlighting because cardiovascular
disease is the leading cause of death in America and other chronic illnesses such as diabetes and
Alzheimers are also found in the top 10.
Cardiovascular disease is a significant contributor to mortality worldwide and it is often
times preventable or controllable. Common examples of cardiovascular disease include
atherosclerosis, stroke, and heart failure. A potent thrombin receptor antagonist, eryloside F, has
been isolated from the sponge Erylus formosus (Senthikumar and Kim 2010). Thrombin is
involved in blood clotting and activation of its receptor plays a role in both atherosclerosis and
arterial thrombosis (Senthikumar and Kim 2010). Another compound, halichlorine, from the
sponge Halichondria okadai, has potential as an atherosclerosis treatment since it inhibits
expression of vascular cell adhesion molecule 1; this molecule may play a critical role in the
build-up of waste deposition inside endothelial artery wall (Kuramoto et al 1996). Eryloside F
and halichlorine are potentially extremely lucrative treatment options of cardiovascular disease if
they advance into clinical trials.
Neurodegenerative diseases such as Alzheimers disease and Parkinsons disease cause
chronic, progressive loss of brain structure and function. Marine drug discovery in this field
focuses on molecules that will have an impact on the nervous system with potential to stimulate
neuronal growth and/or target neurotransmitter receptors (Senthikumar and Kim 2010). The first
marine derived steroidal alkaloid shown to have significant acetyl cholinesterase inhibiting
properties was isolated from the sponge Corticum sp. and has a functionality that falls in line
with current treatment of mild to moderate Alzheimers disease symptoms (Senthikumar and
Kim 2010). The alkaloid hymenialdisine from the sponge Acanthella aurantianca has been
characterized as potential Alzheimers treatment due to its functionality as a tau-protein
phosphorylation inhibitor, potentially reversing the hyperphosphorylation seen in Alzheimers
patients (Senthikumar and Kim 2010). The compound 11-dehydrosinulariolide isolated from the
coral S. flexibilis has exhibited neuroprotective properties through its reduction of 6hydroxydopamine induced cytotoxicity and also anti-inflammatory properties exhibited through
its suppression of nitric oxide synthase and cyclooxygenase-2 (Chen et al 2012). These factors
make 11- dehydrosinulariolide a suitable contender in the clinical pipeline for Parkinsons
disease.
In addition to organic brain disease treatments there are also a few marine derivatives that
have been developed as psychiatric drug treatments and potential neuromodulators. DMXBA is a
synthetic derivative of the alkaloid anabaseine which is found in marine worms (Mayer et al). It
is currently in Phase III trials and awaiting FDA approval as a treatment for schizophrenia. The
compound is neurologically active and has a selective, stimulating effect on central nervous
system 7 nicotinic acetylcholine receptors (Mayer et al 2010). Treatment with DMXBA in

animal models has been shown to improve cognition and deficient sensory gating and
improve survival of rats undergoing experimental hemorrhage (Mayer et al. 2010). The initial
phase 2 study of DMXBA concluded that it was more effective in treating negative effects than
dopamine antagonist antipsychotic drugs when symptoms are treatment resistant (Freedman et al
2008). Keramidine is an alkaloid isolated from the sponge Agelas sp. that shows
neurosuppressive activity via serotonergic receptor antagonism which disrupts neural
transmission in serotonergic pathways (Sipkema et al. 2005). Serotonin has been studied
extensively in the brain and is often linked to a variety of psychiatric disorders such as major
depression and generalized anxiety disorder. As a serotonin modulator, keramidine may have
some potential as a treatment for psychological illnesses. Another sponge derived product is the
unique amino acid dysiherbaine from Dysidea herbacea; it displays potent excitatory action and
induces seizures via the disruption of glutamate balance through high affinity binding to KA
receptors as well as non-NMDA and subtype-selective mGluR agonsim (Sakai et al. 2001).
Current status of marine-derived pharmaceuticals
In the United States there are currently five FDA approved pharmaceuticals that have their origin
in marine life and they are cytarabine, vidarabine, ziconotide, brentuximab vedotin, and eribulin
mesylate. Cytarabine is a cancer treatment developed from the nucleoside spongothymidine and
isolated in the Caribbean sponge Tethya crypta (Mayer et al. 2010). Vidarabine is an anti-viral
that was also isolated in the Tethya crypta but its origins stem from the nucleoside spongouridine
rather than spogothymidine (Mayer et al. 2010). The analgesic ziconotide is a synthetic equal to
the peptide -conotoxin found in the marine snail Conus magus (Mayer et al. 2010). The final
drug, eribulin mesylate, is a synthetic derivative of the cytotoxin halichondrin B. This potent
toxin was first isolated in the sponge Halichondria okadai in 1986 and the synthetic, simplified
analogue gained FDA approval in 2010 as a metastatic breast cancer treatment that works
through a novel mechanism involving microtubule targeting (Montaser and Luesch 2011). In
addition to these FDA approved drugs there are currently 25 compounds in various phases of the
global pharmaceutical pipeline. A large majority of these compounds are being looked at as
various cancer treatments but there are a few, such as tetrodotoxin and DMXBA, which are being
looked at as chronic pain and mental disorder treatments respectively (Mayer et al. 2010).
Challenges to research and future development
Despite an optimistic outlook, marine biomedicine and pharmacology is occasionally faced with
significant challenges that keep the field small and unable to flourish in a way that is
proportional to its prospective impact. One such challenge is simply chemical supply; even if a
marine derived compound is found to be biologically active as a pharmaceutical treatment there
must be a constant supply of the compound or a novel synthesis method to create enough
compound for research that often takes over a decade to complete. Another challenge is the
biochemical characterization of possibly billions of isolated compounds. For every compound
that is biomedically relevant, there may be thousands upon thousands of compounds that show
no relevant biochemical activity in humans. Answers to these challenges will come with time and
the inevitable advancement of research methods and machines.
Current biotechnology is revolutionizing the way scientists discover, analyze, and
produce marine natural products. Affinity chromatography, immunoaffinity fluorescent probes,

protein microarrays, and functional genomic and proteomic profiling are all methods of postphenotypic screen target-identification (Montaser and Luesch 2011). This technique of target
identification is crucial in drug discovery and utilizes phenotypic screens to identify cellular
targets and mechanistic action of compounds; this is extremely useful for sorting through a large
body of possibly inactive marine derived compounds (Montaser and Luesch 2011). Another
recent advancement in biotechnology is genome mining which has been guided by the lowered
cost and increased availability of whole-genome sequencing (Montaser and Luesch 2011). This
approach to drug discovery is based on the idea that a genome can be searched for particular
DNA sequences (genes) which encode biochemically relevant enzymes involved in the synthesis
of a particular peptide (Li et al. 2004). These peptides have known functions and mechanisms
thus making genomic mining a useful resource for the discovery and creation of a supply for
more beneficial, abundant, and perhaps more potent chemical analogues that can be fully
synthesized.
As previously described, coral reef ecosystems are extremely diverse, productive
environments and because of this, exceptionally unique chemicals are often found there that have
the potential to be used in biomedical research. This review will highlight marine derived natural
products in all phases of clinical development that have their origin in reef-dwelling organisms
ranging from bacteria to elasmobranchs. The compounds that will be focused on have been or are
being developed for a wide range of uses including HIV treatments, anti-viral compounds,
antimicrobials, anti-inflammatories, and other assorted products that are relevant to scientific
research as a whole.

Discussion
Coral reef ecosystems hold a great deal of potential for pharmaceutical development and natural
marine products and can be viewed as a largely unexplored frontier with regards to metabolic
biochemistry research. Currently there are only five approved FDA drugs of marine origin plus
the behind-the-counter formulation of Omega-3 fatty acids on the market and this low number
may be deceiving to someone unaware of the sheer unexplored diversity of marine chemicals.
Today there are more marine-derived compounds in the clinical pipeline towards FDA approval
than there were ten years ago which sheds some light on the advances of oceanographic
collection methods and analytic biotechnologies. There are currently 17 compounds in phase I of
clinical trials or between phases I and II. Optimism is key when dealing with novel research and
right now it is evident that the field of marine biomedicine is growing just by looking at past
patterns of clinical trial compounds.
It is important to remember that even if the brightest scientists are working on marine
drug development, they wont be able to do research on coral reefs if the reefs disappear. Current
model predictions are not looking bright for the future in 100 years existing habits of pollution
and antiquity are maintained. If the simple idea that coral reefs must be protected to maintain
global diversity and chemical equilibria isnt enough to tide the population to slow pollution
rates, then the incentive of direct benefit via pharmaceutical and bioactive compound
development should be. The protection of coral reef ecosystems is intertwined with humanitys
ability to not only survive, but thrive, in the future.

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