Mar.Drugs 2014.12 1072 All in all,the association of modern HTS methods and robust NP libraries,representative of a wide biodiversity,is a powerful tool to streamline cosmeceutical and therapeutic lead discovery programs 3.2.Supply and Technical Challenges Several different problems are associated with supply and technical issues.The first one is related to the variability of the organism itself.For instance,taking the example of sponges,the high frequency of their bioactive metabolites is interpreted as chemical defense against environmental stress factors such as predation,overgrowth by fouling organisms or competition for space.The highest incidence of toxic or deterrent sponge metabolites is found in habitats such as coral reefs that are characterized by intense competition and feeding pressure.Because these environmental conditions are not static,it is likely that a resupply of the same organism does not provide the same metabolite.Also, in the case of marine invertebrates another challenge is the fact the microorganisms are sometimes the actual producers of the bioactives Once a particular natural product has been isolated and identified as a lead compound,the issue of its sustainable supply is faced.Most of the times,the compound of interest is present only in low amounts and/or can be very difficult to isolate [17].In the case of tissues of marine invertebrates, which present unique extraction-related problems due to their high water and salt content,this problem can be even more challenging.Whatever the use of the compound (drug cosmetic,rc.).several grams to hundreds of grams are required for preclinical development,multikilogram quantities are needed for clinical phases and tons for cosmetic uses. Mariculture(favoring by farming the growth of the organism in its natural milieu)and aquaculture (culture of the organism under artificial conditions)have been attempted in order to solve the problem of sustainable supply of macroorganisms.However,the unique and sometimesexclusive.conditions of the sea make cultivation or maintenance of the isolated samples very difficult and often impossible. For example,sponges and their microbiota are generally not suitable for cultivation,hence,the compound of interest may need to be extracted and purified from the specimens collected in the wild [47].These constraints lead to the loss of a major portion of the available marine biodiversity and represent a major bottleneck in the sustainable supply of the desired natural compound. This lack of sustainable supply of substances has stopped further development of several highly promising marine compounds,and attempts have been made to overcome this barrier by developing synthetic or hemisynthesic analogues,derivatives with more manageable properties.or by design of a pharmacophore of reduced complexity which can then be synthesized [301.However.it is worth noting.that these approaches embrace themselves their own challenges.Total synthesis is by no means an easy undertaking task,and chemistry still has a very long way to go before it can make any molecule in a practical manner.NP are complex and exquisite molecules possessing,almost always, one or several stereocenters,a fact that renders their synthesis hard to achieve,since enanteo or diastereoselective synthetic or purification processes are difficult to perform.Hemisynthesis may be.in some cases,a good solution for compound's supply.This process involves harvesting a biosynthetic intermediate from the natural source,rather than the lead itself,and converting it into the lead.This approach has two advantages.First,the intermediate may be more easily extracted in a higher yield than the final product itself.Second,it may allow the syntheses of analogues of the final product. Mar. Drugs 2014, 12 1072 All in all, the association of modern HTS methods and robust NP libraries, representative of a wide biodiversity, is a powerful tool to streamline cosmeceutical and therapeutic lead discovery programs. 3.2. Supply and Technical Challenges Several different problems are associated with supply and technical issues. The first one is related to the variability of the organism itself. For instance, taking the example of sponges, the high frequency of their bioactive metabolites is interpreted as chemical defense against environmental stress factors such as predation, overgrowth by fouling organisms or competition for space. The highest incidence of toxic or deterrent sponge metabolites is found in habitats such as coral reefs that are characterized by intense competition and feeding pressure. Because these environmental conditions are not static, it is likely that a resupply of the same organism does not provide the same metabolite. Also, in the case of marine invertebrates another challenge is the fact the microorganisms are sometimes the actual producers of the bioactives. Once a particular natural product has been isolated and identified as a lead compound, the issue of its sustainable supply is faced. Most of the times, the compound of interest is present only in low amounts and/or can be very difficult to isolate [17]. In the case of tissues of marine invertebrates, which present unique extraction-related problems due to their high water and salt content, this problem can be even more challenging. Whatever the use of the compound (drug, cosmetic, etc.), several grams to hundreds of grams are required for preclinical development, multikilogram quantities are needed for clinical phases and tons for cosmetic uses. Mariculture (favoring by farming the growth of the organism in its natural milieu) and aquaculture (culture of the organism under artificial conditions) have been attempted in order to solve the problem of sustainable supply of macroorganisms. However, the unique and sometimes exclusive, conditions of the sea make cultivation or maintenance of the isolated samples very difficult and often impossible. For example, sponges and their microbiota are generally not suitable for cultivation, hence, the compound of interest may need to be extracted and purified from the specimens collected in the wild [47]. These constraints lead to the loss of a major portion of the available marine biodiversity and represent a major bottleneck in the sustainable supply of the desired natural compound. This lack of sustainable supply of substances has stopped further development of several highly promising marine compounds, and attempts have been made to overcome this barrier by developing synthetic or hemisynthesic analogues, derivatives with more manageable properties, or by design of a pharmacophore of reduced complexity which can then be synthesized [30]. However, it is worth noting, that these approaches embrace themselves their own challenges. Total synthesis is by no means an easy undertaking task, and chemistry still has a very long way to go before it can make any molecule in a practical manner. NP are complex and exquisite molecules possessing, almost always, one or several stereocenters, a fact that renders their synthesis hard to achieve, since enanteo or diastereoselective synthetic or purification processes are difficult to perform. Hemisynthesis may be, in some cases, a good solution for compound‘s supply. This process involves harvesting a biosynthetic intermediate from the natural source, rather than the lead itself, and converting it into the lead. This approach has two advantages. First, the intermediate may be more easily extracted in a higher yield than the final product itself. Second, it may allow the syntheses of analogues of the final product