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United States Department of Agriculture

Agricultural Research Service

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Research Project: DISCOVERY AND DEVELOPMENT OF NATURAL PRODUCTS FOR PHARMACEUTICAL AND AGRICHEMICAL APPLICATIONS

Location: Natural Products Utilization Research

2009 Annual Report


1a.Objectives (from AD-416)
The overall goal of this project is to discover, develop and foster commercialization of new bioactive natural products as new pharmaceuticals or agrichemicals, and to identify, characterize, and develop medicinal plants for production of pharmaceuticals as potential alternative crops.


1b.Approach (from AD-416)
The approach includes a program of: (1) Discovery of secondary metabolites from natural resources with anti-infective and anti-cancer activities based on molecular and cell-based assays; (2) Characterizing mechanisms of action, selectivity, toxicity, and functional activity for the best candidate compounds with anti-microbial and anti-cancer properties in secondary assays and in animal models; and, (3) Selection, agronomics and analysis of medicinally important plants and their derived products.


3.Progress Report
Maintained our basic discovery operations, with emphasis on the discovery of antifungals, anticancer, anti-inflammatory agents and immunomodulating agents. Continued to source plant materials for screening from the Missouri Botanical Garden, New York Botanical Garden, Kenya Academy of Sciences, our own plant collections and from a myriad of collaborators. Added 918 plant samples to our inventory this year. Screened over 12,000 natural product crude extracts, semi-purified fractions and purified compounds in 08-09 for biological activities against, specific molecular targets and/or whole cell systems. As part of our continuing effort in the search for anti-infective, anti-cancer, and immunomodulator/anti-inflammatory leads from natural sources, we completed bioassay-guided chemical investigation on more than 25 species for 07-08. As a result, more than 100, including 55 new natural products were identified from plants, marine sponges, and fungi. They showed potent phytotoxic, antifungal, antibacterial, and/or antimalarial activities. Over 40 of our isolated actives have been characterized in more detailed follow-up assays to determine their mode of action, pharmaceutical properties, toxicity, and selectivity across a range of assays. In addition to these basic operations, we have selected a number of these compounds for more advanced study, whether for characterizing mechanisms of action, determining suitability for further pharmaceutical development, or evaluation in disease models in preclinical studies, or in field applications in the case of agrichemicals. We identified 5 new antimalarial leads in the past year, and 7 new antifungal/antibacterial leads that have been scaled up and progressed to animal testing. One synthetic anti-cancer agent has been further tested in animals. Tested the efficacy of several urushiol derivatives [the toxic principle of poison ivy] for desensitization to poison ivy dermatitis. These have been developed under a Small Business Initiative Research (SBIR) grant from the National Institutes of Health (NIH), in collaboration with ElSohly Laboratories, Inc. Two of these hold great promise for developing desensitizing or protective agents. Our “Living Collection” of medicinal plants is about 1,200 species during the 08-09 FY. Also, our seedbank of medicinal plants now stands at 450 species. Demonstration plots of several medicinal herbs are grown each year in our Medicinal Plant Garden. We continued evaluation of 3 Echinacea species with regard to cultivability, yields, and harvesting techniques, as well as endophyte analysis. Field studies were conducted with Smallanthus species [sonchifolius (Yacon) and uvedalia] to explore cultivatibility in this region.

Hydroponic cultures of Stevia were implemented during this year, and studies of resveratrol yields in peanuts were initiated.


4.Accomplishments
1. Antifungal and Antibacterial Natural Products. Antifungal and antibiotic drug resistance is a continuing problem, especially in immunocompromised patients. Plants and other organisms have developed elaborate mechanisms to defend against invading pathogens. Identifying these compounds and understanding their mechanisms of action may lead to new antifungal or antibacterial drugs or agricultural pest control agents. This project has been partially supported by substantial NIH funding for the last 19 years, and many important achievements have resulted, with significant developments in this past year. This project spans from screening and isolation of antifungal compounds from nature through to studies of their mechanisms of action and their potential utility as fungicides and for pharmaceutical applications. Six new isolation projects were supported from this screening, and 10 novel antifungal structures were identified. Three of these compounds have been profiled in mechanistic studies via genomic and genetic techniques. New structures have also been identified that enhance the activity of fluconazole in resistant fungi. A new screen was developed for assessment of extracts that overcome resistance in Vibrio pathogens. These discovered compounds have opened new avenues of research on antifungal drug targets, and to evaluating these classes for their potential as drug leads. Additional National Institutes of Health (NIH) funding supports a new project to study mechanisms of action of these antifungal compounds.

2. Agents for Prevention/treatment of Poison Ivy Dermatitis. Poison ivy dermatitis is a serious problem for wilderness enthusiasts and exposed workers. There is no specific treatment, and at present no effective way to “de-sensitize” individuals who have severe reactions. In the past year, we worked with NIH funding developing new leads that are effective in animals in the prevention of poison ivy dermatitis, developing data in animal models on two leads. One of these gives a very effective and long-lasting desensitization to the poison ivy allergic response. These are in the process of patent coverage. A Phase II SBIR grant from NIH received the top priority score, and will be funded in the summer of 2009. These agents will be considered for development as a desensitizing treatment.

3. Immunostimulant Product from Spirulina. Although it has long been known that Spirulina can have beneficial effects on the immune system, the active constituents have been elusive, and it has been difficult to develop a consistent product. It has also been very difficult to demonstrate impacts of the extract in animal models to guide the development of products for human use. Research at the NCNPR, University of Mississippi, has identified an active fraction of the Spirulina and developed a way to standardize the extract based on a specific macrophage activation test in vitro. The standardized extract is now marketed as Immulina in Europe and ImmunXT in the U.S. This product was used by scientists at Louisana State University (LSU) in a mouse model of H1N1 infection. The developers of this extract at the NCNPR designed this study to determine if oral ingestion of this extract for a month before infection and for 21 days post-infection could lessen some of the pathology accompanying H1N1 infection. Mice treated with Immulina exhibited statistically significant reductions in clinical symptoms and lung damage due to infection and lost substantially less weight than mice in the control group. This further demonstrates the efficacy of this product to stimulate the immune system and prevent the impact of viral infection in this model. This will pave the way for further studies of utility of this type product in infectious diseases, and perhaps in cancer models as well.

4. Immunostimulant Activity in Botanicals. Although it has long been known that several botanical products [e.g., Echinacea, Alfalfa, Ginseng] can have beneficial effects on the immune system, the active constituents have been elusive, and it has been difficult to develop a consistent product. Researchers at the NCNPR, University of Mississippi, have identified active fractions of Echinacea and several other botanicals, based on a specific macrophage activation test in vitro. Recent findings from this past year indicate that endophytic bacterial lipoproteins and lipopolysaccharides account for a large fraction of the macrophage stimulating activity. This work has dramatic implications for our understanding of immune modulation by botanicals, whether as part of the diet, or used as supplements. These findings open new research frontiers in understanding the biosynthesis and production of the immunostimulant activity, in understanding variability of these plants, and in outlining mechanisms of action in human and animal health.

5. Natural Product Antimalarial and Antileishmanial Drug Leads. Malaria is a disease which kills more than two million people every year, especially the children in tropical regions of the world. The disease has attracted significant global attention due to its high health as well as economic impacts. Leishmaniasis is endemic worldwide with estimated 12 million cases, which are mostly centered in Asia, Mediterranean regions of Europe, Africa, Central America and South America. This objective was achieved through continued in vitro screening of diverse libraries of natural and synthetic compounds obtained through the collaborators within the school of pharmacy and external sources. More than 20 natural products extracts were identified, and the pure compounds with potent antimalarial activity were isolated. Four of the new lead compounds were advanced through a critical path paradigm especially in vivo evaluation in mouse malaria models. These new lead compounds have been added to the antimalarial drug discovery pipeline for further evaluation. One class was selected and several synthetic analogs were prepared. Genomic and functional characterization of molecular targets, which were valuable in developing a molecular targets-based strategy for new antimalarial drug discovery. One patent has been filed concerning the antiprotozoal activities of one of the consituents of honey mesquite. The screening efforts were useful in attracting significant external funding for research in this area, especially from the US Army Medical Research and Materiel Command. This funding has been useful in development of consortium on “models for human glucose 6-phosphate dehydrogenase deficiency”, which would be utilized for development of non-hemolytic 8-aminoquinoline antimalarial drugs. Another Dept of Defense-funded project focuses on natural products for discovery of new anti-leishmanial agents.


Review Publications
Stanikunaite, R., Radwan, M.M., Trappe, J.M., Fronczek, F., Ross, S.A. 2008. Lanostane-Type Triterpenes from the Mushroom Astraeus pteridis with Antituberculosis Activity. Journal of Natural Products. 71(12):2077-2079.

Samoylenko, V., Jacob, M.R., Khan, S.I., Zhao, J., Tekwani, B.L., Midiwo, J.O., Walker, L.A., Muhammad, I. 2009. Antimicrobial, Antiparasitic and Cytotoxic Spermine Alkaloids from Albizia schimperiana. Natural Product Communications. 4(6):791-796.

Samoylenko, V., Ashfaq, M.K., Jacob, M.R., Tekwani, B.L., Khan, S.I., Manly, S.P., Joshi, V.C., Walker, L.A., Muhammad, I. 2009. Indolizidine, Antiinfective and Antiparasitic Compounds from Prosopis glandulosa var. glandulosa. Journal of Natural Products. 72(1):92-98.

Zhao, J., Dasmahapatra, A.K., Khan, S.I., Khan, I.A. 2008. Anti-Aromatase Activity of the Constituents from Damiana (Turnera diffusa). Journal of Ethnopharmacology. 120:387-393.

Ross, S.A., Rodriguez-Guzman, R., Radwan, M.M., Jacob, M., Ding, Y., Li, X., Ferreira, D., Manly, S.P. 2008. Sorocenols G and H, Anti-MRSA Oxygen Heterocyclic Diels-Alder-type Adducts from Sorocea muriculata Roots. Journal of Natural Products. 71(10):1764-1767.

Samoylenko, V., Khan, S.I., Jacob, M.R., Tekwani, B.L., Walker, L.A., Hufford, C.D., Muhammad, I. 2009. Bioactive (+)-Manzamine A and (+)-Hydroxymanzamine A Tertiary Bases and Salts from Acanthostrongylophora ingnes and Their Preparations. Natural Product Communications. 4(2):185-192.

Ding, Y., Li, X., Ferreira, D. 2009. Theoretical Calculation of Electronic Circular Dichroism of a Hexahydroxydiphenoyl-Containing Flavanone Glycoside. Journal of Natural Products. 72(3):327-335.

Kamel, H.N., Ding, Y., Li, X., Ferreira, D., Fronczek, F.R., Slattery, M. 2009. Beyond Polymaxenolide: Cembrane-Africanane Terpenoids from the Hybrid Soft Coral Sinularia maxima x S. polydactyla. Journal of Natural Products. 72:900-905.

Stanikunaite, R., Khan, S.I., Trappe, J.M., Ross, S.A. 2009. Cyclooxygenase-2 Inhibitory and Antioxidant Compounds from the Truffle Elaphomyces granulatus. Phytotherapy Research. 23:575-578.

Samoylenko, V., Dunbar, D., Gafur, M., Khan, S.I., Ross, S.A., Mossa, J.S., El-Feraly, F.S., Tekwani, B.L., Bossalaers, J., Muhammad, I. 2008. Antiparasitic, Nematicidal and Antifouling Constituents from Juniperus Berries. Phytotherapy Research. 22:1570-1576.

Pradhan, A., Mukherjee, P., Tripathi, A.K., Avery, M.A., Walker, L.A., Tekwani, B.L. 2009. Analysis of Quaternary Structure of a [LDH-like] Malate Dehydrogenase of Plasmodium falciparum with Oligomeric Mutants. Molecular and Cellular Biochemistry. 325:141-148.

Khan, M., Levi, M.S., Tekwani, B.L., Khan, S.I., Kimura, E., Borne, R.F. 2009. Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs. Antimicrobial Agents and Chemotherapy. 53(4):1320-1324.

Last Modified: 9/21/2014
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