Marine Biotechnology in the Twenty-First Century Problems, Promise, and Products (2002) / Chapter Skim
Currently Skimming:
Session 1: Drug Discovery and Development
Session 1: Drug Discovery and Development
Pages 45-64
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 45... ...
~tiorz of Ocearzography Nature has been the traditional source for organic chemical compounds used in medicine. For over 3,000 years, early societies recognized that their immediate environments were a rich source of plants that provided methods to treat ordinary infections, inflammation, arthritis, cancers, and many human diseases.
|
From page 46... ...
Given the enormous biodiversity of the world's oceans, it is unfortunate that marine environments are the last great frontier for investigation. Unfortunately, with the pressures of economics weighing heavily on the pharmaceutical industry, natural product-based drug discovery has been characterized as encumbered and overly time consuming.
|
From page 47... ...
MARINE NATURAL PRODUCTS AS A RESOURCE FOR DRUG DISCOVERY: OPPORTUNITIES AND CHALLENGES Guy 2C Carter, Ph.D. Director, Natural Products Chemistry arldf Discovery Analytical Chemistry Wyeth-Ayerst Research It has been stated that the "search and discovery of exploitable biology" is undergoing a "paradigm shift" as a "consequence of the bioinformatics
|
From page 48... ...
A major obstacle to the discovery of new marine natural products with promising biological activities is simply the difficulty of having them evaluated in a wide range of targeted assays. Although new therapeutic targets are being developed at an astonishing rate, ability to evaluate marine chemodiversity in these assays is severely limited.
|
From page 49... ...
One example, illustrative of both the challenges and opportunities, is the case of microorganisms isolated from the tropical marine ascidian Polysyncraton lithostrotum.
|
From page 50... ...
spectrum of positive assay results led to the most promising candidate, characterized as a halophilic micromonospora species that produced potent DNA-damaging activity. Pilot plant scale fermentation of the organism, tentatively named M
|
From page 51... ...
Many of the real or perceived bottlenecks to marine natural productsbased drug discovery are founded on the issue of whether sufficient material will be available for complete biological and chemical evaluation and eventual production. Obviously, the development of synthetic and biosynthetic methods for production are real challenges, which must be addressed.
|
From page 52... ...
. Many other novel compounds have been isolated and characterized chemically, and preliminary biological testing indicates that they are interesting lead compounds for the future development of drugs for a wide variety of human diseases.
|
From page 53... ...
Although Taxol and vinca alkaloids are both derived from terrestrial plants, their development is a prime example of how the advocacy and developmental process works. The history of Taxol in modern medicine starts over 30 years ago with the collection of samples of the Pacific yew tree by the U.S.
|
From page 54... ...
54 MARINE BIOTECHNOLOGYIN THE TWENTY-FIRST CENTURY TABLE 4 A Sampling of Undeveloped Marine Compounds with Significant Indications of Efficacy Marine Potential Source Compounds Uses Reference Sponge Onnamide F Antifungal, antinem Vuong et al., 2001 Trachyclad? vs atode worm Sponge Aka Kynureninase inhibitors serotonin sulfate Neuroprotectants Feng et al., 2000 for use in AIDS dementia and stroke Cyanobacterium Hermitamides Anticancer Tan et al., 2000 Lyngbya A, B Sponge Axisonitrile-3 AntiTuberculosis Konigetal., 2000 Sea whip Pseudopteroxazole AntiTuberculosis Rodriguez et al., Pseudopterogorgia 1 999 Sponge Ircinia Cheilanthane Kinase inhibitors, Buchanan et al., sesterterpenoids multiple uses 2001 Fungus Oxepinamide Antiinflammatory Belofsky et al., 2000 Acremonium Fungus Fumiquinazoline Antifungal Belofsky et al., 2000 Acremonium Natural source Polycyclic acridines Drug resistant lung Stanslas et al., 2000 cancer Hydroid TridentatolA Antioxidantinhibits Johnson etal., 1999 LDL lipid peroxidation (superior to vitamin E)
|
From page 55... ...
We have found that although there are important differences between the actions of Taxol and the vinca alkaloids involving their effects on microtubule mass at high drug concentrations, at another mechanistic level, surprisingly, they act similarly to suppress microtubule dynamics (Wilson and Jordan, 1995; Jordan and Wilson, 1998; Jordan, 20011. Both classes of drugs, the microtubule stabilizers and the microtubule depolymerizers, act at very low but physiologically relevant concentrations to stabilize the dynamics of microtubules in dividing cells.
|
From page 56... ...
1998. In vitro antiviral activity on dengue virus of marine natural products.
|
From page 57... ...
Journal of Natural Products 59:710716. ECOLOGICAL ROLES: MECHANISMS FOR DISCOVERY OF NOVEL TARGETS, COMPARATIVE BIOCHEMISTRY Patrick/.
|
From page 58... ...
This presentation examines how the principles of studying species diversity that are central to comparative biochemistry and physiology might be further applied to the field of marine natural products discovery. Many examples of the August Krogh principle now exist in comparative biology and medicine, and the generally accepted notion of the utility of marine and freshwater animal models of human disease states and processes was recently reviewed in the National Research Council's report Monsoons to Microbes (NRC, 19991.
|
From page 59... ...
in biomedical research, aquatic organisms offer opportunities to conduct at least some naturalprod(ncts-related~research in a much more cost-e~ective antisocially acceptable manner. Returning to the first point, I'd like to propose that for several reasons the species diversity in the marine environment itself may be a desirable source of experimental variation for the organisms upon which natural products are tested.
|
From page 60... ...
However, given the much larger genetic palette of aquatic organisms to choose from, the chances of finding a test organism with an identical or nearly identical mutation to a human SNP increases dramatically. Thus, one might use a species from the marine environment that is noted for being susceptible to the side effects of a drug to do some initial screens to see what human subpopulations might have problems.
|
From page 61... ...
. The state of genome research for some representative aquatic species will be presented, and one topic of discussion might be what species should be further targeted for research that will make them useful to natural products discovery.
|
From page 62... ...
The field of combinatorial biosynthesis exploded after the realization that natural procluct-basecl chemical libraries can be created through biotechnology ancl that the field has the potential to dramatically alter the way natural product drug leads are investigated ancl developed (Hutchinson, 19981. The approach involves the expression of secondary metabolic biosynthetic genes from one or more systems in an alternative host to create unnatural metabolic pathways that result in the production of"unnatural" natural products (Cane et al., 19981.
|
From page 63... ...
Given that marine invertebrates can be rare, difficult to collect, and slow growing and that their removal from the environment might have negative consequences, marine biotechnology is well positioned to circumvent these problems through the cultivation of symbionts and the genetic engineering of biosynthetic machinery in heterologous hosts. Molecular phylogenetic analyses of the microflora of marine sponges from different oceans, for instance, have recently revealed uniform microbial communities distinct from marine plankton or sediments (Hentschel et al., submitted)
|
From page 64... ...
64 MARINE BIOTECHNOLOGYIN THE TWENTY-FIRST CENTURY Acknowledgments Research on exploring and engineering natural products diversity from marine microorganisms in the author's laboratory is generously supported by the National and Washington Sea Grant Programs (R/B-28 and R/B39) , the National Institutes of Health (AI47818)
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.