1986 — 1988 |
Gerwick, William H |
R23Activity Code Description: Undocumented code - click on the grant title for more information. |
Antineoplastic Agents From Blue Green Algae @ Oregon State University
We have isolated two series of novel natural products from two Caribbean blue-green algae, Anabaina oscillarioides and Microcoleus lyngbyaceus. All of these secondary metabolites show good in vitro cytotoxicity and one, for which we have unambiguously assigned a novel styrylchromone structure, shows excellent cytotoxicity with ID50 values in the nanogram range. Further, this latter natural product selectively inhibits RNA synthesis in two cancerous cell lines. Our subsequent collections of these same two blue-greens from different habitats and seasons have pointed out the extreme chemical variability of these life forms. The extracts of these latter collections are strongly biologically active yet contain very different chemistry by TLC analysis than the previous collections. The above observations lead us to propose a systematic investigation of these and other Caribbean blue green algae for new cytotoxins. Further, we plan to explore the influence of environmental factors on blue green algal secondary metabolism by seasonal collections and labaoratory culture work. Our long term objectives are to discover new chemotherapeutic agents for treating neoplastic diseases, and hence, to further understand the structural requirements for cellular toxicity.
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0.901 |
1989 |
Gerwick, William H |
S15Activity Code Description: Undocumented code - click on the grant title for more information. |
Small Instrumentation Program @ Oregon State University
biomedical equipment resource; biomedical equipment purchase;
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0.901 |
1990 |
Gerwick, William H |
F06Activity Code Description: Undocumented code - click on the grant title for more information. |
Eicosanoid Biosynthesis in Marine Plants @ Oregon State University |
0.901 |
1997 — 1999 |
Gerwick, William H |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Antineoplastic Agents From Marine Microalgae @ University of California Santa Cruz
The strategy of this proposal is to develop and use innovative approaches, based on new understanding of tumor biology and the molecular understanding of cancer, to discover chemotherapeutics effective in treating solid tumors of the breast, prostate, ovary, lung and colon. The goal of this laboratory program of our NCNPDDG project will be to use these assays to discover new lead compounds from field collected marine cyanobacteria and macroalgae as well as cultured marine microalgae. The long term objective of this research is to use innovative biochemical and cell-based assays to discover and describe structurally-novel natural products as anticancer lead compounds from marine macroalgae and microalgae. The specific aims of this work are to: 1) to evaluate approximately 1000- 1200 extracts of various field collected or cultured marine micro- and macro-algae over a 5 year period in a series of innovative biochemical and cell-based assays available at Sandoz Pharmaceutical, 2) to fractionate active extracts from the above screening efforts, following activity with either the biochemical or cell-based assays, as appropriate, to obtain pure natural products which are potential anticancer leads, 3) to elucidate the structures of pure active compounds using spectrochemical techniques, 4) to continue the scaled-up culture of active species or re-collection of tuft-forming or macroalgal species and re-isolation of active compounds to provide samples for pharmacologic and clinical investigation, 5) to produce semi-synthetic analogs of active compounds for exploration of structure-activity relationships in new lead compounds, and 6) to obtain patent coverage on promising antitumor natural products and their derivatives. The methodologies for collection of marine microalgae from the tropics and macroalgae from the tropics as Well as temperate locations will use shallow water field collection techniques in use in our laboratory. Aqueous and lipid extracts will be evaluated in innovative biochemical and cell based assays with our collaborators at Sandoz. Isolation of the active compounds will be followed with the biochemical assays, and a palate of spectrochemical methods emphasizing two-dimensional nuclear magnetic resonance will be used to solve the structures of the new anticancer lead compounds. Recollections or recultures will provide samples of new cancer lead compounds for in-depth biochemical and in vivo evaluations.
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0.91 |
1999 — 2002 |
Gerwick, William H |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Combinatorial Biosynthetic Libraries From Cyanobacteria @ University of Minnesota Twin Cities
The overall goal of this Laboratory Program is to produce libraries of natural product-derived substances by innovative methods and to evaluate these in "Smart" bioassay systems targeted to cancer. Despite intensive effort in many fields of science and medicine to find effective treatments for this complex family of diseases, the incidence and morbidity due to cancer continues to look very bleak. This Laboratory Program will focus on the unique chemistries of marine cyanobacteria, and will integrate with the efforts of the other laboratory programs of this Program Project Grant application to clone natural products biosynthetic genes and over express these in a convenient host organism, Streptomyces venezuelae. Four parallel tracks will be taken in this pursuit: 1) our laboratory will provide cultured marine cyanobacteria to Laboratory Program #1 for genomic DNA insolation and subsequent combinatorial biology efforts in Laboratory Program #2; 2) our laboratory will provide information to Laboratory Program #2 on biosynthetic pathways and partial protein sequences of key "tailoring" enzymes to aid in the cloning of genes of specific marine cyanobacterial metabolites of high relevance to cancer and diversity generation; 3) our laboratory will integrate with Novartis "Smart" assays (Laboratory Program #3) to isolate and structurally define new lead compounds deriving from the above integrated molecular biological approaches; and 4) our laboratory will use unique tailoring enzymes cloned from marine cyanobacteria and modified by protein engineering techniques to biotransform additional natural product structures of cancer relevance. Diode-array HPLC methods will be used to dereplicate parent structures, known compounds, and nuisance substance in the combinatorial biosynthetic libraries showing activity in the Novartis "Smart" assays.
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0.915 |
2001 — 2015 |
Gerwick, William Henry Murray, Thomas F (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurotoxins From Marine Algae and Cyanobacteria @ University of California San Diego
DESCRIPTION (provided by applicant): Natural products have played pivotal roles in neuropharmacology due to their potent and selective targeting of specific biochemical pathways and receptors, and are highly useful as probe substances and therapeutic leads. Marine cyanobacteria are exceptionally rich in diverse natural product structures, many of which are toxic or have other biological properties. We propose to continue our productive collaboration between a natural products chemist (Gerwick) and a neuropharmacologist (Murray), expanding on our previous investigations of these life forms for their new and biologically-insightful neuroactive compounds. Thus, we have the long range goals of 1) developing new compounds to serve as novel tools for pharmacology and cell biology, 2) describing new putative environmental toxins so that appropriate actions can be taken should outbreaks occur, and 3) development of neuroactive substances as potential therapeutic lead compounds, especially in the treatment of stroke-induced brain injury. To accomplish these goals we have the following four specific aims: 1) to collect 250 samples of cyanobacteria and algae, and produce high quality focused fraction libraries for screening in assays designed to detect neuroactive natural products, 2) to evaluate the above diverse extracts using high throughput spontaneous Ca2+ oscillation and Na+ influx assays in cerebrocortical neurons, 3) to use innovative and accelerated methods to isolate and structurally characterize new neuroactive substances from marine cyanobacteria testing positively in the screening assays, featuring nanoscale NMR and MSn methods, 4) to further define the molecular pharmacology of several cyanobacterial toxins discovered during prior support. Additionally, to evaluate the influence of newly discovered cyanobacterial ligands on neurite outgrowth, spinogenesis and synaptogenesis in neocortical neurons. Select compounds active in these in vitro assays will be advanced into a mouse model for focal stroke. This will require the production of additional supplies or analogs of these newly discovered compounds, including radioisotope-labeled analogs to be used in radioligand binding and distribution assays. Completion of these aims will increase our knowledge of the unique and neuroactive natural products produced by marine cyanobacteria and algae. The past two cycles of support for this collaborative program have been highly productive, and we now have a mature, well functioning, and highly effective program. We continue to refine our approaches and thinking as applied to the discovery and utility of novel marine neuroactive substances, and this leads us in new research directions for the proposed coming grant period, such as the application of voltage-gated sodium channel activators that promote neurite outgrowth in neocortical neurons to the potential treatment of stroke-induced brain injury.
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0.912 |
2003 |
Gerwick, William H |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Us-Japan Seminar On Marine Bioorganic Chemistry @ Oregon State University
DESCRIPTION (provided by applicant): A marine bioorganic and natural products chemistry joint U.S. - Japan Seminar, entitled "Marine Bioorganic Chemistry: Biological Origins, Functions and Applications", is proposed to be held near Osaka, Japan on June 22-27, 2003. This Joint Seminar will include 29 speakers and seven observers from Japan and the United States. The venue will be at the Awaji Yumebutai International Conference Center, Japan which is located near to the Kansai International Airport (Osaka). The first Seminar occurred seventeen years ago and constituted an important first step for increasing interaction between marine chemistry-oriented research groups from these two countries. It is generally agreed that U.S. and Japanese researchers are contributing seminal ideas in marine bioorganic chemistry, so this Seminar will provide an important opportunity to bring together top researchers. The Seminar format will emphasize the presentation and discussion of ideas which will undoubtedly underlie future research to be conducted in this field, and will necessarily stimulate new bilateral collaborations on this important biomedical topic. The list of participants includes representatives from major academic, industrial, and government laboratories, and provides a balance of established investigators, individuals at early stages of their careers, minorities and women. The specific aims of the conference application are: 1. To conduct a Seminar on the frontiers of marine bioorganic chemistry and biotechnology involving both U.S. and Japanese participants. 2. To conduct the meeting near Osaka, Japan on June 22-27, 2003, organized in the U.S. by Professor William Gerwick, College of Pharmacy, Oregon State University; and in Japan by Professor Daisuke Uemura, Graduate School of Science, Nagoya University. 3. To bring 14 participants and 3 observers from the U.S. plus 15 participants and 4 observers from Japan together so they can engage in both formal and informal discussions on frontier issues in marine bioorganic and natural products chemistry.
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0.901 |
2003 — 2007 |
Gerwick, William H |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Bioassay and Ecology Directed Drug Discovery in Panama @ Smithsonian Institution
DESCRIPTION (provided by applicant): This is a renewal application to continue our ICBG efforts in Panama which combine the goals of drug discovery from natural sources with host country infrastructure development, training, economic growth, biodiversity inventories, and conservation. The past 4.5 years have been highly productive in all of these areas, with the majority of effort occurring in the host country and at host country institutions. Panama possesses an extraordinary biodiversity of plants and algae owing to its unique juxtaposition between North and South America and between the Caribbean Sea and the Pacific Ocean. As such, Panama is a "biodiversity hotspot" as well as a biological corridor between these major geographical features, thus providing unique opportunities for high impact regional and international conservation strategies. We have assembled a remarkable team from Panamanian and US academic institutions as well as leaders in the pharmaceutical and agrochemical industries. We propose a team effort to explore the natural products of diverse terrestrial plants, marine algae and cyanobacteria for compounds active to several tropical diseases, (leishmaniasis, Chagas' disease, and malaria) cancer (cell- and mechanism-based) and agricultural pests. Our ecological approach to selecting plants for collection, as well as a processing strategy, which preserves biologically active materials, yields a higher rate of active extracts than otherwise expected. Our conservation efforts involve leading institutions such as the Smithsonian Tropical Research Institute, Conservation International, and the Woods Hole Oceanographic Institution. Our program has very positive interactions with, and support from, host country institutions, and through our outreach efforts we continue to improve the perceived value of biodiversity by Panamanians. The two collaborating companies (Novartis and Dow AgroSciences), one focused on pharmaceuticals and the other on agrochemicals, provide additional biotesting, financial and training resources, as well as a mechanism for the development of promising materials. All collection and bioassay information is maintained on a web database, and this insures excellent access by all team members as well as host country and US government partners. A well-developed set of legal documents assures a highly beneficial plan for intellectual property and benefit sharing with Panama.
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0.948 |
2005 — 2009 |
Gerwick, William Henry |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
New Approaches to Anticancer Agents From Cyanobacteria @ University of California Santa Cruz
The overarching goal of this project is to discover new natural products with anticancer applications from marine cyanobacteria and algae using mechanism-based assays against epigenetic targets. Tropical shallow water benthic cyanobacteria and algae have been rich taxonomic groups for the production of medicinally-relevant natural products. However, the majority of the ocean's cyanobacteria and many macroalgae have been little sampled and largely overlooked in previous anticancer drug discovery programs, mainly because most species attain little biomass under natural conditions. One important and underlying hypothesis being examined in this proposed work is that marine cyanobacteria belonging to many genera other than those studied to date will also be rich in their production of anticancer-type natural products. The specific aims which lead to this long term goal are: 1. To access previously unstudied marine cyanobacteria and macroalgae through examination of new habitats and new strategies for their collection and culture 2. To apply improved and innovative paradigms to enhance the detection of bioactive compounds from cyanobacterial/macroalgal extracts, including prefractionation and pure compound library formation 3. To screen marine cyanobacterial and algal derived compounds and reduced complexity mixtures for anticancer-type activities at Novartis (NIBR) using contemporary mechanism-based screening against epigenetic targets 4. To derepticate nuisance compounds through application of combined LC-MS and Microcoil NMR profiling procedures 5. To isolate and structurally define cyanobacterial and algal metabolites that are active in the NIBR mechanism-based assays using HPLC followed by efficient NMR and MS methodologies 6. To scale-up the isolation of active compounds to assist NIBR drug development efforts using recollection, culture, genetic-based methods, or synthetic/semi-synthetic methods, as appropriate and efficient 7. To patent notable discoveries and publish all results in the peer-reviewed literature.
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0.91 |
2008 — 2011 |
Gerwick, William H |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Icbg: "Training, Conservation and Drug Discovery Using Panamanian Microorganisms @ Smithsonian Institution
DESCRIPTION (provided by applicant): DESCRIPTION (provided by applicant): The over-arching goal of this work is to discover new lead compounds from Panamanian microorganisms for the treatment of cancer, CNS disorders, tropical diseases, and agricultural pests, employing a spectrum of innovative as well as traditional bioassays. This pursuit will be inextricably connected to the development of scientific training and capacity building in a biodiversity-rich yet economically-developing country, and will foster tangible results in biodiversity conservation and infrastructure development. The specific aims of this proposal which will allow us to reach these goals are: 1) Use ecological concepts to guide the collection and culture of endophytic fungi, cyanobacteria and other heterotrophic bacteria within the biodiversity-rich country of Panama, 2) Produce extracts of these collected and cultured materials and prefractionate these by appropriate techniques to produce reduced complexity screening units which have active ingredients in increased titer, 3) Through efforts of personnel in AP2 plus our collaborators, to perform biological screens of extracts, prefractionated extracts, and pure compounds in the following therapeutic areas: Cancer, Central Nervous System biology, Agriculture, and Tropical diseases (malaria, leishmania and Chagas'disease), 4) Utilize an integrated approach of taxonomy, computer databases, and LC-MS data to rapidly and efficiently dereplicate known and nuisance compounds at early stages in the discovery process, 5) Isolate active compounds identified in the above assay areas using bioassay-guided approaches, and to characterize these substances using efficient and modern spectroscopic methods, 6) Inventory the biodiversity of terrestrial plants and marine algae in Panama, and to continue to build the permanent floral collections in Panama, 7) Evolve and maintain the formal contracts between all of the participants in this program to address intellectual property rights, promote equitable sharing of benefits, and to facilitate broad access to the data and results of these research endeavors, 8) Help build the scientific infrastructure and expertise necessary to support a sustainable drug discovery program based in Panama, and 9) Integrate our drug discovery and conservation efforts to develop innovative new economic products from the biodiverse marine and terrestrial habitats of Panama. This proposal seeks to discover new medicines from Panama's rich biodiversity of terrestrial and marine microorganisms. The focus of our discovery efforts are new treatments for cancer, CNS disorders, and tropical diseases as well as agricultural chemicals.
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0.948 |
2010 — 2019 |
Gerwick, William Henry |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training Program in Marine Biotechnology @ University of California, San Diego
? DESCRIPTION (provided by applicant): Training Program in Marine Biotechnology This renewal application for a Training Program (TP) in Marine Biotechnology at UC San Diego represents the third cycle of requested support for this unique program. As a discipline, marine biotechnology has seen considerable advancement in recent years with an increasing number of valuable products being derived from or inspired by marine life forms. Hence, this TP has the goal of training a diverse workforce with the appropriate multidisciplinary education to work at the confluence of marine science, organic chemistry, biochemistry, pharmacology, genomics, cell biology, and computational science. In this immediately past cycle of 4 years, we demonstrated that the program could operate as envisioned by both the TP leadership and the NIH with a superb group of highly talented and enthusiastic trainees, one---third of whom are members of underrepresented minority groups. These trainees are participating in a robust curriculum in Marine Biotechnology, involved in a student---run invited seminar speaker program and year---end research retreat, have completed their Responsible Conduct in Research training on time, and have engaged in the unique Industrial Internship feature of the program during their period of NIH trainee support. In this renewal application, four senior faculty no longer involved in graduate student training have retired from the TP, and five new and diverse faculty in sciences related to marine biotechnology have been added. This Training Program has developed considerable campus recognition, and is highly appreciated and supported by campus administration, including generous matching funds as detailed in this proposal and support letters. The proposed path forward for this TP in the next cycle involves additional solidification of the policies and procedures of this training program, further enhancement of our underrepresented minority and people with disabilities recruitment, and refinement of the running of the program with greater use of our External Advisory Committee and other participant feedback.
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0.912 |
2011 — 2012 |
Gerwick, William Henry Hook, Vivian Y. H. [⬀] La Spada, Albert R |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Huntington's Disease Natural Product Drug Discovery @ University of California San Diego
DESCRIPTION (provided by applicant): Huntington's Disease (HD) is a neurological disorder resulting from CAG triplet repeat genetic mutation of the IT15 gene that encodes the huntingtin protein. Extensive data in the field indicate that proteolytic fragment(s) of htt mediate the HD disease process, resulting in severe motor disturbances. The goal of this project will be to discover novel marine natural product compounds as potential therapeutic agents for Huntington's disease (HD). This project fulfills a major gap in the HD and neurodegenerative disease field for discovery of novel agents as protease inhibitors for future development of therapeutic agents for HD. Furthermore, this project uses novel marine natural products as a unique opportunity for drug discovery in the protease target area to reduce production of neurotoxic htt proteolytic fragments that participate in HD. This unique project will integrate expertise in protease biochemistry and neurobiology by Dr. Vivian Hook, marine natural products for discovery of therapeutic agents by Dr. William Gerwick, and model striatal neuronal cells, as well as transgenic mice, expressing mutant huntingtin (htt) protein of Huntington's disease by Dr. Albert La Spada at the Univ. of Calif., San Diego. The project plan will implement interdisciplinary efforts of three highly experienced laboratories in the required disciplines to discover novel protease inhibitors of huntingtin protein proteolysis as a means to reduce cellular mutant htt neurotoxicity. This project can progress at a rapid pace since the collaborating laboratories have the required expertise, and are located in close proximity to one another at UC San Diego. HD drug discovery of this project will be accomplished in two specific aims. The first aim will evaluate marine natural product compounds for inhibition of protease activities thought to be involved in HD, which includes caspase, calpain, lysosomal proteases (cathepsins L, B, and D), and matrix metalloprotease 10. Cyanobacteria algal marine natural product compounds are a rich source of potent drug molecules with unique structural diversity. In aim 2, cyanobacterial marine natural compounds will be tested in cellular assays for reduction of N-terminal htt fragments and protection from cell death, using striatal-like neuronal cells that express full-length mutant huntingtin (htt) protein, and in control cells expressing normal htt protein. Effective compounds identified from aims 1 and 2 will be prioritized by their inhibitory potencies. These compounds will be planned for a future R01 project that will conduct in vivo testing of compounds in HD mouse models for effectiveness to improve the motor impairment in HD transgenic mice. Results can indicate candidate marine natural drug compounds for HD drug development.
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0.912 |
2011 — 2015 |
Gerwick, William H Sherman, David H [⬀] Sherman, David H [⬀] Smith, Janet L. (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Biosynthetic Analysis of Marine Cyanobacterial Pathways
DESCRIPTION (provided by applicant): Marine cyanobacteria are extraordinarily rich in their production of biologically active and structurally unique natural products. A number of these secondary metabolites or their derivatives are lead compounds in drug development programs aimed at providing new therapies to treat cancer, bacterial infections, inflammatory responses and in crop protection to kill harmful microbial pathogens and insects. Isolation and structural analysis of marine and terrestrial cyanobacterial natural products has provided access to an unusually large number of mixed non-ribosomal peptide synthetase/polyketide synthase (NRPS/PKS) systems. The corresponding metabolic systems are comprised of an intriguing set of complex multifunctional proteins that along with allied enzymes generate structurally complex molecules via a modular multi-step process. Over the past several years the Sherman, Gerwick and Smith laboratories have developed a complementary program to clone and characterize the biosynthetic pathways of novel cyanobacterial secondary metabolites that possess significant potential for biotechnological applications. Despite considerable progress, a full understanding of the molecular mechanisms, catalytic activities, kinetic properties, and substrate specificities within cyanobacterial biosynthetic pathways is just beginning to unfold. The proposed research will build upon our accomplishments on the curacin, jamaicamide and cryptophycin/ arenastatin metabolic systems, three robust pathways that have been a rich source of new information. The expected metabolic, biochemical and structural understanding will facilitate the design of new biosynthetic systems that harness the growing potential of cyanobacterial natural product pathways. The full promise of cyanobacterial natural products to yield new lead compounds for development as useful pharmaceuticals will only be realized by closing a series of key gaps in knowledge and technology. Solving these challenges will require development and optimization of genetic and biochemical methods that allow us to 1) manipulate cyanobacterial natural product metabolic systems to produce analog structures, 2) utilize unique secondary metabolite enzymes for creation of novel bioactive molecules and, 3) screen new compounds and analogs to identify promising new anticancer compounds for further development. The specific aims are: 1. To harness the inherent versatility of cyanobacterial natural product systems to create new anticancer lead compounds. Sub-aims include: a. Investigate ability of cyanobacterial biosynthetic pathways to generate novel analogs using unique laboratory culture and mutasynthesis methodologies. b. Investigate the unique enzymatic capabilities of marine cyanobacterial pathways to engineer new metabolic systems and tailoring processes to generate new bioactive compounds. c. Employ structural biology and site-directed mutagenesis approaches to understand the precise biochemical mechanisms of unique biosynthetic enzymes. d. Develop new chemoenzymatic, in vivo, and in vitro pathways to create new anticancer agents with enhanced medicinal properties 2. Perform bioassays on new compounds resulting from Specific Aim 1. a. New compounds derived from the proposed research will be transferred to Eisai Research Institute and University of Michigan Center for Chemical Genomics for analysis of biological activity using a series of biochemical and cell based assays relevant to cancer. PUBLIC HEALTH RELEVANCE: The proposed research will focus on elucidating the detailed function and mechanistic basis of complex biosynthetic pathways from marine cyanobacteria that create chemically diverse natural products with anti-cancer activity. The ability to understand and subsequently engineer these remarkable biochemical systems will create new opportunities to discover and develop effective drugs for the treatment of human diseases, particularly cancer and related metabolic disorders.
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0.909 |
2012 — 2013 |
Gerwick, William Henry |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Icbg: 'Training, Conservation and Drug Discovery Using Panamanian Microorganisms @ Smithsonian Institution
DESCRIPTION (provided by applicant): DESCRIPTION (provided by applicant): The over-arching goal of this work is to discover new lead compounds from Panamanian microorganisms for the treatment of cancer, CNS disorders, tropical diseases, and agricultural pests, employing a spectrum of innovative as well as traditional bioassays. This pursuit will be inextricably connected to the development of scientific training and capacity building in a biodiversity-rich yet economically-developing country, and will foster tangible results in biodiversity conservation and infrastructure development. The specific aims of this proposal which will allow us to reach these goals are: 1) Use ecological concepts to guide the collection and culture of endophytic fungi, cyanobacteria and other heterotrophic bacteria within the biodiversity-rich country of Panama, 2) Produce extracts of these collected and cultured materials and prefractionate these by appropriate techniques to produce reduced complexity screening units which have active ingredients in increased titer, 3) Through efforts of personnel in AP2 plus our collaborators, to perform biological screens of extracts, prefractionated extracts, and pure compounds in the following therapeutic areas: Cancer, Central Nervous System biology, Agriculture, and Tropical diseases (malaria, leishmania and Chagas' disease), 4) Utilize an integrated approach of taxonomy, computer databases, and LC-MS data to rapidly and efficiently dereplicate known and nuisance compounds at early stages in the discovery process, 5) Isolate active compounds identified in the above assay areas using bioassay-guided approaches, and to characterize these substances using efficient and modern spectroscopic methods, 6) Inventory the biodiversity of terrestrial plants and marine algae in Panama, and to continue to build the permanent floral collections in Panama, 7) Evolve and maintain the formal contracts between all of the participants in this program to address intellectual property rights, promote equitable sharing of benefits, and to facilitate broad access to the data and results of these research endeavors, 8) Help build the scientific infrastructure and expertise necessary to support a sustainable drug discovery program based in Panama, and 9) Integrate our drug discovery and conservation efforts to develop innovative new economic products from the biodiverse marine and terrestrial habitats of Panama. This proposal seeks to discover new medicines from Panama's rich biodiversity of terrestrial and marine microorganisms. The focus of our discovery efforts are new treatments for cancer, CNS disorders, and tropical diseases as well as agricultural chemicals.
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0.948 |
2013 — 2016 |
Dorrestein, Pieter C (co-PI) [⬀] Gerwick, Lena Gerwick, William Henry |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mapping the Secondary Metabolomes of Marine Cyanobacteria @ University of California San Diego
DESCRIPTION (provided by applicant): Key to the process of pharmaceutical lead compound discovery from natural sources is the effective access and characterization of highly diverse molecular structures. In this regard, exploration of the marine environment for bioactive natural products is revealing new vistas in natural products chemical diversity. In this application we propose the development of innovative technologies and knowledge, principally based on LC-MS/MS data and 'molecular mapping', which will improve the effectiveness of natural products drug discovery efforts. This will enable a much improved capacity to discover new molecular diversity or analogs in desired structure classes. We will develop an understanding of the degree of expression of natural product pathways in cultured strains, and will develop novel methods by which to upregulate low or non-expressing biosynthetic gene clusters. As a result of these studies, new marine cyanobacterial natural products will be discovered and their biomedical properties will be characterized. To accomplish these goals we have the following four specific aims: 1) To use LC-MS/MS profiling of cyanobacterial extracts and pure compounds, followed by molecular mapping, to create a representation of the chemical universe of our samples. 2) To use QPCR and genome sequencing technologies to evaluate the degree of expression of natural product pathways in our cultured marine cyanobacteria, and to connect Natural Product Super-producing strains of cyanobacteria with their genotypes. This latter information can be used to find genetic markers that can be rapidly deployed to locate this phenotype in new cyanobacterial cultures and collections. 3) To use a suite of imaginative methods to transcriptionally activate cryptic natural product biosynthetic gene clusters in strains determined in Aim 2 to possess un-expressed natural products capacity, and to analyze the resulting elicited secondary metabolomes by mass spectrometry and molecular mapping. 4) To isolate members of new families of compounds detected in Aims 1, as well as newly expressed natural products from Aim 3, and rigorously establish molecular structures using advanced analytical methods. Through the course of these four specific aims, this collaborative group will explore a number of innovative methods and approaches in the natural products sciences, including MS/MS molecular mapping, genomic analysis of natural products expression, elicitation of new natural products expression, connection of natural product-rich phenotypes to their corresponding genotypes, imaging mass spectrometry of complex consortiums of species wherein natural product pathways are activated, and novel automated MS approaches to natural products characterization. All of these methods are focused on improving the detection and characterization of the molecular diversity present in microorganisms, in this case, marine cyanobacteria. This molecular diversity continues to be an important source of inspirational molecules for biomedical research and drug discovery.
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0.912 |
2017 — 2018 |
Gerwick, William Henry Siqueira-Neto, Jair Lage |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Development of Gallinamide a-Inspired Agents For the Treatment of Chagas? Disease @ University of California San Diego
A compelling need exists to find more efficacious medicines with which to treat Chagas? Disease, especially the chronic stages for which there is no effective treatment. Chagas? Disease is caused by a parasitic trypanosome that afflicts millions in the tropical Americas and more than 300,000 in the US. Moreover, with climate change there are changing patterns of parasitic diseases such as Chagas? Disease, and this is certain to affect an increasing number of American citizens in the future. Our laboratories have discovered an exquisitely potent anti-Chagas agent from a marine cyanobacterium that targets the unique protease of this parasite, namely ?cruzain?. Cruzain represents a chemically and genetically validated target within this parasite. Moreover, this natural product as well as synthetic analogs have the ability to clear myoblast cells of infection with no significant host cell cytotoxicity. In this application we plan to advance this drug class to meet this unmet medical need in eukaryotic parasitic diseases, and this will be accomplished in two phases. Three specific aims in the R21 phase will allow synthesis and re-synthesis of several gallinamide A analogs designed previously from a modeling study, establish critical initial PK parameters and allow proof of concept efficacy testing. We have developed an effective synthetic route for this compound as well as 16 analogs based on extensive optimization of two published synthetic routes, insuring an adequate supply of the compounds. This is a rare starting point for a drug development effort in which a natural product can be sustainably produced and the molecular target in the parasite is known. In the R33 phase, we will further explore a second generation of model-inspired gallinamide A analogs through chemical synthesis, expand our evaluation of their ADME, PK, MTD and efficacy evaluations, and then test our best lead compounds in a chronic curative mouse model. A set of clear metrics have been devised by which to evaluate progress and success in both the R21 and R33 phases of the project. At the conclusion of this project, we anticipate delivery of a late stage preclinical lead for the treatment of Chagas? Disease which will have a robust profile of chemical, biochemical, pharmaceutical and efficacy information.
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0.912 |
2017 — 2020 |
Gerwick, Lena Gerwick, William Henry Golden, James William [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Development of An Efficient Cyanobacterial Platform For Heterologous Expression and Biosynthetic Interrogations of Natural Products. @ University of California, San Diego
Project Summary This project will overcome a main obstacle impeding progress to fully exploit marine natural products (NPs) for health applications. Currently, there are no efficient genetic methods to interrogate and modify endogenous NP biosynthetic pathways from marine filamentous cyanobacteria, and no robust platforms for heterologous expression and genetic engineering of cyanobacterial NP pathways. This project will develop methods and tools for engineering cyanobacteria for the heterologous expression and manipulation of NP gene clusters identified in organisms that are not amenable to genetic methods, or orphan NP gene clusters that are identified in environmental DNA sequences. The project will use the synthetic-biology strain Synechococcus elongatus PCC7942 and the marine filamentous cyanobacterium Leptolyngbya (ISB-3N94-8PLP) to provide two distinct but complementary genetic platforms for the expression and engineering of NP pathways. The long-term objectives of this project are to provide efficient platforms for the production of NPs in quantities suitable for studying their biological activities and for chemical modifications to enhance those activities for health applications. Although a few relatively simple marine cyanobacterial NPs have been produced in heterologous hosts such as E. coli, difficulties remain for the expression certain enzymes and of large complex pathways in phylogenetically distant hosts. We hypothesize that expression of these cyanobacterial genes and gene clusters in cyanobacterial hosts will overcome this obstacle. The 3 specific aims of this research are as follows. (1) Establish Leptolyngbya as a broadly applicable genetic platform for identification, expression, and interrogation of NP pathways. (2) Develop improved genetic tools to enable the transfer, refactoring, and overexpression of large biosynthetic pathways in platform strains of cyanobacteria. (3) Express two orphan pathways from the marine cyanobacterial genus Okeania in S. elongatus and Leptolyngbya. New genetic tools and methods will be created for S. elongatus and Leptolyngbya that will include TAR cloning vectors, shuttle plasmids, chromosomal integration sites, constitutive and regulated promoters, reporter genes, and antibiotic-resistance markers to facilitate manipulation of endogenous NP pathways and for the heterologous expression of pathways from other organisms. This project will combine state-of-the-art approaches in genomics, transcriptomics, bioinformatics of secondary metabolite pathways, cyanobacterial genetic engineering, and NP chemistry to address knowledge gaps related to medically important NP biosynthesis in marine cyanobacteria. The project will develop Leptolyngbya and S. elongatus into broadly useful expression hosts for cyanobacterial secondary-metabolite enzymes and entire NP biosynthetic pathways, and these hosts and genetic tools will be made available to the NP research community.
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0.912 |
2017 — 2021 |
Cottrell, Garrison W (co-PI) [⬀] Dorrestein, Pieter C (co-PI) [⬀] Gerwick, Lena Gerwick, William Henry |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Tools For Rapid and Accurate Structure Elucidation of Natural Products @ University of California, San Diego
Mapping the Secondary Metabolomes of Marine Cyanobacteria Bacteria are extraordinarily prolific sources of structurally unique and biologically active natural products that derive from a diversity of fascinating biochemical pathways. However, the complete structure elucidation of natural products is often the most time consuming and costly endeavor in natural product drug discovery programs. Compounding this, advancements in genome sequencing have accelerated the identification of unique modular biosynthetic gene clusters in prokaryotes and revealed a wealth of new compounds yet to be isolated and biologically and chemically characterized. Resultantly, there is an urgent and continuing need in this field to connect biosynthetic gene clusters to their respective MS fragmentation signatures in the MS2 molecular networks. The capacity to make such connections will accelerate new compound discovery as well as create associations between gene cluster and biosynthetic pathway, and aid in fast and accurate structure elucidations. Combined with this informatics approach, this proposed continuation project explores innovative methods by which to solve complex molecular structures by enhanced MS and NMR experiments, as well as the development of new algorithms by which to accelerate their analysis. Thus, the overarching goal of this grant is to develop efficient methods that facilitate automated structural classification, structural feature discovery and ultimately efficient structure elucidation of natural products (or any small molecule) and to build an infrastructure that interacts with data input from the community. We will achieve this with the following four specific aims: Aim 1. Integration of MS2 molecular networking with gene cluster networking to rapidly and efficiently locate natural products that have unique molecular architectures; Aim 2. To develop a suite of high sensitivity pulse sequences for natural product structure elucidation; Aim 3. To develop NMR based molecular networking strategies using Deep Convolutional Neural Networks (DCNNs) to facilitate the categorization and structure elucidation of organic compounds; Aim 4. To integrate NMR molecular networking and MS2-based molecular networking as an efficient structure characterization and elucidation strategy. By achieving these aims we will develop an innovative workflow for finding new compounds and for determining their structures, both quickly and accurately. The connection between gene cluster and molecule will shed light on stereochemistry and potential halogenations and methylations. This information can then be used in combination with more efficient NMR and MS methods to accurately determine structures. These tools will be widely shared, such as through the Global Natural Products Social (GNPS) Molecular Network, to enhance the overall capacity of the natural products and organic chemistry communities to solve complex molecular structures.
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0.912 |
2021 |
Cottrell, Garrison W (co-PI) [⬀] Dorrestein, Pieter C (co-PI) [⬀] Gerwick, Lena Gerwick, William Henry |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Unified Computation Tools For Natural Products Research @ University of California, San Diego
Summary The overarching goal for this proposed renewal application will be to further advance tools that are in development and to effectively integrate several types of analytical data with biological assay data and genomic information. This will create a powerful set of tools for faster and even more accurate identification of new molecules, dereplication of known ones, and to directly infer biological activities from spectroscopic information. In the current period of support, we have made substantial progress in developing highly useful tools for automatic annotations and identifications of organic molecules, specifically focused on natural products. The Global Natural Products Social (GNPS) Molecular Networking analysis and knowledge dissemination ecosystem has processed almost 160,000 jobs in nearly 160 countries worldwide, has 4-6,000 new job submissions per month and is accessed over 200,000 times a month (majority accessions are for reference library access, inspection of public data and previous jobs that the community shares as hyperlinks in papers), and has become a mainstream tool for the annotation of organic molecules deriving from diverse sources, especially in metabolomics workflows. The public website for Small Molecule Accurate Recognition Technology (SMART), a deep learning model for providing candidate structures based on 1H-13C HSQC NMR data, went live in December 2019 and already has over 3000 jobs in 50 countries. All tools developed in this proposal will become part of this analysis ecosystem. The four laboratories contributing to this proposed research activity have created an open and integrated team that is continuing to creatively innovate new informatic tools to enhance small molecule structure annotations and inference of their chemical and biological properties. We have four specific aims: 1) To complete the development and evaluation of a set of new and innovative tools for natural products analysis, and deploy these as freely available resources for the worldwide community. 2) To refine the structural characterization of molecules through leveraging repository scale mass spectral information along with NMR data and genomic inputs. 3) To create a new SMART-based tool that integrates mass spectrometry and HSQC NMR data as the input for a new deep learning system with the goal of achieving more accurate predictions of structure. 4) To use deep learning to enhance SMART with bioactivity data so as to enable SMART to predict activities of molecules based on spectroscopic features. The data will also augment the GNPS database with biological assay binding data. An additional consequence of these goals will be the further digitization of natural products analytical data so that they can be used in the computational tools planned herein, as well as other tools in the future. Completion of these four specific aims will create new integrated tools for the precise identification of new natural product structures, and enable inference of their structural relatedness to other classes of organic molecules and their biological properties. Thus, these new informatic tools will have the potential to greatly enhance the small molecule drug discovery process.
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0.912 |