Part F | 29.5
720 Part F Marine Derived Metabolites
29.5 Marine Natural Products: New and Recurrent Challenges
29.5.1 Facing Supply Obstacles:
Advances and Strategies
Marine natural products have yielded actual and
promissory novel molecules with biological activity
and an opportunity for the discovery of drugs. Besides the achievements reached so far, marine natural
products face many difficulties. Indeed, the relation of
bioactive molecules to biomass is not always enough
to ensure an adequate supply for pursuing drug development based on a natural product. Bioprospecting
is a key issue in this context of using natural marine
compounds and at the same time protecting the source
organism and its habitat from overexploitation. In some
ways, a balance between sustainability and conservation is desired when collecting target marine organisms
as natural product source material. However, the development of preclinical in vivo evaluation assessment of
marine natural products has been hampered by a lack
of material. Inventive solutions to the supply problem
of these and other marine natural products with therapeutic properties may ultimately determine their future
use, even if clinical outcomes are favorable [29.11].
Indeed, the supply issue concerning obtaining drugs
from marine natural products and sustainable production, is still is an obstacle to be overcome and is one
of the limiting and recurrent challenges for most pharmacologically active marine natural products, which
can only be isolated in minute yields [29.94] (Table 29.2). The limited supply or large-scale exploitation
can destroy the environment, and the complexity of
the molecular structures in many cases makes the synthesis unfeasible. Currently, the methods of production
include: large-scale collections, aquaculture, chemical
synthesis, fermentation, and genomics (Table 29.3).
The selection of the proper method to obtain any marine natural product will depend on the characteristics
or complexity of the compounds of interest and their
source [29.86].
Table 29.2 Limiting factors of marine derived therapeutics
drugs (after [29.2])
Potential limiting factors of marine therapeutics drugs
Sustainable supply of clinical and industrial activities
Preclinical pharmacokinetics, bioavailability and half life
Pharmacogenetics, metabolic pathways
Physiological dose/therapeutics index
Toxicities, formation of possible metabolites
Among the available strategies biotechnology is an
option for the production of bryostatins through the
mariculture of the bryozoan Bugula neritina (ET-743)
and the tunicate Ecteinascidia turbinate. However,
again, this strategy is not feasible due to the costs
associated with the destruction of culture facilities
and stocks by storms and oceanographic phenomena
or by diseases, which make production predictability
unsure and unsafe. Total synthesis has been successfully established for halichondrin B, ET-743, bryostatins, and others, but in many cases has resulted
in being economically infeasible due to the complexity of the molecular structures and the low yields of
the final products achieved. For example, 1 t of the
sponge Lissodendoryx sp. yields 300 mg of halichondrin analogs [29.95]. Contrary to this, the peptide !conotoxin MVIIA (SNX-111) from the marine mollusk
Conus magus, known under the generic name of Ziconotide, can be obtained through synthesis in virtually
unlimited amounts [29.16, 94].
When chemical synthesis is not feasible, and given
the limited availability and regulation of marine resources, it is clear that product supply could never
be completed successfully by these methods [29.94,
96]. In E. turbinate, nearly 1 t (wet weight) needs to
be harvested in order to obtain approximately 1 g of
ET-743 [29.97]. Another option is partial synthesis
from precursors that are biotechnologically available,
as in the case of ET-743, obtained through 21-step
synthesis from the marine bacterium Pseudomonas fluorescens. However, a low overall yield of 1:4% was
obtained because the starting material was generated
by fermentation [29.86], a finding that exemplifies the
process developed by a Spanish pharmaceutical company. Some bioactive compounds can be produced by
Table 29.3 Strategies to supply marine-derived therapeutics for clinical and industrial development (after [29.2,
10])
Potential limiting factors of marine therapeutics drugs
Natural habitats, controlled use of natural resources
Hemisynthesis: use or related compounds as starter followed
by an industrial synthetic process
Aquaculture (on land) and mariculture by farming in natural
milileu
Synthesis
Fermentation
Genomics/metagenomics
720 Part F Marine Derived Metabolites
29.5 Marine Natural Products: New and Recurrent Challenges
29.5.1 Facing Supply Obstacles:
Advances and Strategies
Marine natural products have yielded actual and
promissory novel molecules with biological activity
and an opportunity for the discovery of drugs. Besides the achievements reached so far, marine natural
products face many difficulties. Indeed, the relation of
bioactive molecules to biomass is not always enough
to ensure an adequate supply for pursuing drug development based on a natural product. Bioprospecting
is a key issue in this context of using natural marine
compounds and at the same time protecting the source
organism and its habitat from overexploitation. In some
ways, a balance between sustainability and conservation is desired when collecting target marine organisms
as natural product source material. However, the development of preclinical in vivo evaluation assessment of
marine natural products has been hampered by a lack
of material. Inventive solutions to the supply problem
of these and other marine natural products with therapeutic properties may ultimately determine their future
use, even if clinical outcomes are favorable [29.11].
Indeed, the supply issue concerning obtaining drugs
from marine natural products and sustainable production, is still is an obstacle to be overcome and is one
of the limiting and recurrent challenges for most pharmacologically active marine natural products, which
can only be isolated in minute yields [29.94] (Table 29.2). The limited supply or large-scale exploitation
can destroy the environment, and the complexity of
the molecular structures in many cases makes the synthesis unfeasible. Currently, the methods of production
include: large-scale collections, aquaculture, chemical
synthesis, fermentation, and genomics (Table 29.3).
The selection of the proper method to obtain any marine natural product will depend on the characteristics
or complexity of the compounds of interest and their
source [29.86].
Table 29.2 Limiting factors of marine derived therapeutics
drugs (after [29.2])
Potential limiting factors of marine therapeutics drugs
Sustainable supply of clinical and industrial activities
Preclinical pharmacokinetics, bioavailability and half life
Pharmacogenetics, metabolic pathways
Physiological dose/therapeutics index
Toxicities, formation of possible metabolites
Among the available strategies biotechnology is an
option for the production of bryostatins through the
mariculture of the bryozoan Bugula neritina (ET-743)
and the tunicate Ecteinascidia turbinate. However,
again, this strategy is not feasible due to the costs
associated with the destruction of culture facilities
and stocks by storms and oceanographic phenomena
or by diseases, which make production predictability
unsure and unsafe. Total synthesis has been successfully established for halichondrin B, ET-743, bryostatins, and others, but in many cases has resulted
in being economically infeasible due to the complexity of the molecular structures and the low yields of
the final products achieved. For example, 1 t of the
sponge Lissodendoryx sp. yields 300 mg of halichondrin analogs [29.95]. Contrary to this, the peptide !conotoxin MVIIA (SNX-111) from the marine mollusk
Conus magus, known under the generic name of Ziconotide, can be obtained through synthesis in virtually
unlimited amounts [29.16, 94].
When chemical synthesis is not feasible, and given
the limited availability and regulation of marine resources, it is clear that product supply could never
be completed successfully by these methods [29.94,
96]. In E. turbinate, nearly 1 t (wet weight) needs to
be harvested in order to obtain approximately 1 g of
ET-743 [29.97]. Another option is partial synthesis
from precursors that are biotechnologically available,
as in the case of ET-743, obtained through 21-step
synthesis from the marine bacterium Pseudomonas fluorescens. However, a low overall yield of 1:4% was
obtained because the starting material was generated
by fermentation [29.86], a finding that exemplifies the
process developed by a Spanish pharmaceutical company. Some bioactive compounds can be produced by
Table 29.3 Strategies to supply marine-derived therapeutics for clinical and industrial development (after [29.2,
10])
Potential limiting factors of marine therapeutics drugs
Natural habitats, controlled use of natural resources
Hemisynthesis: use or related compounds as starter followed
by an industrial synthetic process
Aquaculture (on land) and mariculture by farming in natural
milileu
Synthesis
Fermentation
Genomics/metagenomics