Drugs and Leads from the Ocean Through Biotechnology 29.2 Approved Marine Drugs as Pharmaceuticals 713
Part F | 29.2
All these successful examples represent an important
effort by joint ventures of pharmaceutical companies
with scientists and government, as succinctly described
below.
An unfair comparison with conventional drugs on
the market with a long history of research and development, in some cases discourages primary initiatives
and high expectations for drugs from the sea. However,
the best is yet to come, if we consider all the experience gained during these almost 50 years, which in
some way is reflected in the approved products and in
the impressive pipeline of marine-derived compounds
in clinical and preclinical trials, suggesting that several more marine drugs, should soon be approved for
pharmaceutical use [29.10]. In some way, as part of
a relatively recent area, viz, marine biotechnology, and
the integrated efforts of other disciplines may contribute
to new developments, and on the focus on deep sea micro and macroorganisms as sources of natural products
and of novel bioactivities. Actual progress in genomics,
metagenomics, manipulation of biosynthetic pathways,
and combinatory chemistry are promising new discoveries of pharmaceutical lead drugs. The integration,
with other areas and applications of biotechnology will
contribute to the development of this important area of
marine biotechnology.
In this review, recent developments, mainly during the last decade, of marine natural products and
the respective metabolites, are emphasized, considering their interesting biological properties and actual
developments as approved marine-derived drugs and
promissory compounds. The high degree of innovations
per se from marine natural products, have led and will
lead to a resurgence of new drugs and pharmaceutical
applications for new and recurrent challenges of modern human diseases.
An important aspect of this chapter is the analysis
of marine natural products in relation with other disciplines, such as genomics, combinatorial chemistry,
metabolic pathways, and functional foods. Some are
cases of success, others offer great potential application
in other areas of biotechnology and the bioindustry.
29.2 Approved Marine Drugs as Pharmaceuticals
A high number of marine-derived chemical entities with
biological activity in different therapeutic settings has
been discovered during the last couple of decades. Advances and proven evidence of a positive therapeutic
index indicates a favorable tolerability profile in the
different clinical settings assessed. In addition, a number of approaches incorporating target-based discovery
models are yielding to the identification of novelties
with therapeutic potential in a number of diseases. Finally, selected interactions with other thematic fields
are expected to emerge in the near future, and to lead
to new developments in genome mining, biosynthetic
pathways of gene holders and functional foods, and
to contribute to changing the way that marine-derived
drugs are discovered, thus making a significant contribution to welfare and cure of human diseases.
There are actually several excellent reviews on
marine natural products and the respective pharmacology [29.10, 11]; we intend to succinctly emphasize
fundamental and particular issues that will contribute to
the integration and advancement of this innovative discipline and the respective drug pipeline in the context of
biotechnology. It is our conviction that these initiatives
will rapidly develop and expand in different approaches
of human interest over the next decade.
29.2.1 !-Conotoxin MVIIA:
An Analgesic for Neuropathic Pain
The !-conotoxins are poisons produced by piscivorous
cone snails, originally isolated from Conus magus by
Olivera and coworkers in 1979 [29.2]. These toxins
are highly selective antagonists of N-type voltage-gated
calcium channels (VGCCs)voltage-gated calcium channels [29.12, 13]. The venom of this gastropod mollusc,
is a combination of 100200 peptides (length from
9100 amino acids), which exert inhibitory effects on
the neuromuscular system of their prey [29.14, 15].
!-Conotoxin MVIIA is a linear 25 amino acid, polycationic peptide containing six cysteine residues linked by
three disulphide bridges that stabilize its well-defined
three-dimensional structure [29.11] (Fig. 29.1). Compared to difficulties of chemical synthesis in other
marine natural products, the complete synthesis of this
peptide was successfully concluded in 1987 [29.12].
Subsequent studies on this toxin led to the identification that N-type voltage-sensitive calcium channels
(NVSCCs) were its target site. The pharmacological activity of conus-derived toxins is currently used
for its classification, viz, ˛-conotoxins are antagonists
of both muscle and neuronal-type nicotinic acetyl-
Part F | 29.2
All these successful examples represent an important
effort by joint ventures of pharmaceutical companies
with scientists and government, as succinctly described
below.
An unfair comparison with conventional drugs on
the market with a long history of research and development, in some cases discourages primary initiatives
and high expectations for drugs from the sea. However,
the best is yet to come, if we consider all the experience gained during these almost 50 years, which in
some way is reflected in the approved products and in
the impressive pipeline of marine-derived compounds
in clinical and preclinical trials, suggesting that several more marine drugs, should soon be approved for
pharmaceutical use [29.10]. In some way, as part of
a relatively recent area, viz, marine biotechnology, and
the integrated efforts of other disciplines may contribute
to new developments, and on the focus on deep sea micro and macroorganisms as sources of natural products
and of novel bioactivities. Actual progress in genomics,
metagenomics, manipulation of biosynthetic pathways,
and combinatory chemistry are promising new discoveries of pharmaceutical lead drugs. The integration,
with other areas and applications of biotechnology will
contribute to the development of this important area of
marine biotechnology.
In this review, recent developments, mainly during the last decade, of marine natural products and
the respective metabolites, are emphasized, considering their interesting biological properties and actual
developments as approved marine-derived drugs and
promissory compounds. The high degree of innovations
per se from marine natural products, have led and will
lead to a resurgence of new drugs and pharmaceutical
applications for new and recurrent challenges of modern human diseases.
An important aspect of this chapter is the analysis
of marine natural products in relation with other disciplines, such as genomics, combinatorial chemistry,
metabolic pathways, and functional foods. Some are
cases of success, others offer great potential application
in other areas of biotechnology and the bioindustry.
29.2 Approved Marine Drugs as Pharmaceuticals
A high number of marine-derived chemical entities with
biological activity in different therapeutic settings has
been discovered during the last couple of decades. Advances and proven evidence of a positive therapeutic
index indicates a favorable tolerability profile in the
different clinical settings assessed. In addition, a number of approaches incorporating target-based discovery
models are yielding to the identification of novelties
with therapeutic potential in a number of diseases. Finally, selected interactions with other thematic fields
are expected to emerge in the near future, and to lead
to new developments in genome mining, biosynthetic
pathways of gene holders and functional foods, and
to contribute to changing the way that marine-derived
drugs are discovered, thus making a significant contribution to welfare and cure of human diseases.
There are actually several excellent reviews on
marine natural products and the respective pharmacology [29.10, 11]; we intend to succinctly emphasize
fundamental and particular issues that will contribute to
the integration and advancement of this innovative discipline and the respective drug pipeline in the context of
biotechnology. It is our conviction that these initiatives
will rapidly develop and expand in different approaches
of human interest over the next decade.
29.2.1 !-Conotoxin MVIIA:
An Analgesic for Neuropathic Pain
The !-conotoxins are poisons produced by piscivorous
cone snails, originally isolated from Conus magus by
Olivera and coworkers in 1979 [29.2]. These toxins
are highly selective antagonists of N-type voltage-gated
calcium channels (VGCCs)voltage-gated calcium channels [29.12, 13]. The venom of this gastropod mollusc,
is a combination of 100200 peptides (length from
9100 amino acids), which exert inhibitory effects on
the neuromuscular system of their prey [29.14, 15].
!-Conotoxin MVIIA is a linear 25 amino acid, polycationic peptide containing six cysteine residues linked by
three disulphide bridges that stabilize its well-defined
three-dimensional structure [29.11] (Fig. 29.1). Compared to difficulties of chemical synthesis in other
marine natural products, the complete synthesis of this
peptide was successfully concluded in 1987 [29.12].
Subsequent studies on this toxin led to the identification that N-type voltage-sensitive calcium channels
(NVSCCs) were its target site. The pharmacological activity of conus-derived toxins is currently used
for its classification, viz, ˛-conotoxins are antagonists
of both muscle and neuronal-type nicotinic acetyl-