Research Terms
Center of Excellence in Biomedical and Marine Biotechnology
Director |
Amy Wright |
Phone | 772-242-2459 |
Website | https://fau.edu/hboi/mbbr/ |
Mission | The mission of the Center of Excellence in Biomedical and Marine Biotechnology is to establish a coordinated program involving academia and industry aimed at developing Florida’s marine biota as a pharmaceutical resource. The Center brings together groups with established expertise in ocean engineering, marine biotechnology, functional genomics and bioinformatics in a synergistic fashion with the overall goal of discovering and developing new medicines. The Center will establish core laboratories with capabilities in genomics and proteomics, and will create training programs at the pre-doctoral and post-doctoral levels. These activities will attract new businesses to south Florida and provide the highly skilled work force necessary to sustain Florida’s growing biotechnology industry. A central objective of the Center is to transfer technology related to marine drug discovery to the industrial sector. |
Neopeltolide, an active marine-derived macrolide compound shows anti-cell proliferative activities in vitro that could be use primarily in the treatment of cancer also in the treatment of multi-drug resistant cancer cells, secondarily in the treatment of fungal infections preferably in mammal then for the control of fungi growth in spoilage of food, in cosmetic and other consumer items.
In 2014, about 1,665,540 new cancer cases are expected to be diagnosed in the U.S. and about 585,720 are expected to die of cancer, almost 1,600 people per day. Cancer is the second most common cause of death in the US. Cancer is characterized by an accelerated and uncontrolled multiplication of a set of aberrant cells which lose their apoptotic ability. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling the growth of, for example, tumors, new methods and antitumor chemical compositions are needed, as well as in multi-drug resistance (MDR).
Infestations in humans, animals and plants have increased, with many having lethal consequences. There are growing needs amongst others in controlling fungi. Fungi are highly resistant microbiological eukaryotic microorganisms. On the one hand, increased use of antibiotics and immunosuppressive drugs are major factors contributing to higher frequency of fungal infections in immunocompromised patients. One the other hand, chemical fungicides have raised environmental and safety concerns (oncogenic nature, teratogenic effects on human and soil pollution) and the regulation of food safety has become more stringent for avoiding food poisoning. While certain methods and chemical compositions have been developed that aid in inhibiting or controlling the growth of fungi, new methods and new effective antifungal compounds or compositions are needed.
The technology is a bioassay-guided fractionation of an anti-cell proliferation compound, neopeltolide - a biologically active macrolide from an ocean sponge - that shows utility in inhibiting cancer cells and fungal growth.
The inventors have shown that neopeltolide compound have potent anti-tumor and anti-fungal activities. It extends to the compositions with the compound, its enantiomeric forms in excess, its analogues and its derived-salts. Neopeltolide compound is useful for inhibiting pathological cellular proliferation in primary end-use of the treatment of cancer as well as in the treatment of multi-drug resistant cancer cells, secondary in the treatment of fungal infections preferably in mammal then for the control of fungi growth in spoilage of food, in cosmetic and other consumer items.
As example, neopeltolide has a cytotoxic activity on tumoral cells candidates (A549 human lung adenocarcinoma, NCI-ADR RES, and P388 murine leukemia cell lines) with IC50 values respectively of 1.17nM, 5.1nM and 0.56nM). Also, against a fungi candidate, Candida albicans, neopeltolide reaches its minimum inhibitory concentration (MIC) at 0.625 pg/ml.
This is a sustaining technology that could bring great value by offering a natural alternative for the control of fungi and for the treatment of the multi-drug resistance (MDR) or multidrug resistance-associated protein (MRP) cases.
The primary field of use of the technology is the treatment of cancer. The expansion of new drugs in oncology represents one of the most promising objectives of the pharmaceutical industry. Indeed, across 2013, fifteen new molecular entities were approved by the FDA; out of which seven were for oncology. Currently targeted therapies dominate the oncology pipeline, followed by chemotherapy. The market landscape is highly competitive; however, the need for novel anti-tumor compounds is high.
The secondary field of use is in the development of antifungal products:
U.S. Patent US 7179828 B2 Biologically active neopeltolide compounds Issued on Feb 20th, 2007.
Amy E. Wright, Ph.D. (UC, Riverside) is Research Professor and Director of the Center for Marine Biomedical and Biotechnology Research at Harbor Branch Oceanographic Institute, Florida Atlantic University. She has conducted research, for the past 25 years, in the field of natural products chemistry. Her primary research interests focus on the purification and structure identification of naturally occurring compounds which may have utility in treating cancer. Much of the research focuses on the investigation of deep-sea invertebrates collected using the Johnson-Sea-Link human- occupied submersibles. Over the course of her career, her research group has identified over 100 different marine natural products with biological activity. One compound she identified early in her career has been approved in Europe for the treatment of soft tissue sarcoma.
Shirley A. Pomponi, Ph.D. (University of Miami) is Research Professor and Executive Director of the NOAA Cooperative Institute for Ocean Exploration, Research, and Technology at Harbor Branch Oceanographic Institute, Florida Atlantic University. Her research focuses on marine biotechnology, in general, and sponge systematics, cell and molecular biology, in particular. She has authored or co-authored more than 100 peer-reviewed scientific publications and is co-inventor on several patents.
Peter J. McCarthy, Ph.D. (University of Kent, Canterbury, UK) is Research Professor at the Center for Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute, Florida Atlantic University. His research focuses on the discovery of novel natural products and enzymes produced by heterotrophic marine-derived microorganisms.
Oncology, Fungal infection, Food microbiology, Autoimmune Diseases and Inflammatory Diseases.
Microsclerodermins are cyclic peptides derived from marine sponges, which can inhibit cancer cell growth and growth of cells caused by autoimmune and inflammatory diseases.
In the US, cancer is responsible for 25% of all deaths. Death from cancer is primarily due to overgrowth and metastasis of cancer cells to other organs followed by secondary tumor formation throughout the body. Despite improved treatment options, cancer remains a devastating illness. Anticancer drugs directed against the microtubule, including taxanes and vinca alkaloids, have been the backbone of many chemotherapy regimes for decades. However, these drugs have significant limitations to improving patient treatment response including hypersensitivity reactions, neurotoxicity, and the emergence of drug resistance, which have prompted the need for novel microtubule targeting agents. Ideally, novel agents would bind with enhanced tumor specificity, be insensitive to chemoresistance, and reduce neurotoxicity.
The inventors have isolated a new class of naturally occurring microsclerodermins from marine sponges of the Lithistid (Theonella, Microscleroderma, and Amphibleptula genera) and Pachastrellidae families. These cyclic peptides posses unusual amino acids, which can inhibit cancer cell growth (microsclerodermin F) as well as unwanted cell growth related to autoimmune disorders and inflammation. Specifically, they may inhibit growth of tumors in the breast, colon, CNS, liver, lung, as well as leukemia or melanoma cells. They may also be active against ovarian, uterine, renal, pancreatic, and prostate cancer. These compound block mitosis of tumor cell lines and have a number of cellular effects including disruption of the tubulin matrix. They can be readily modified into analogs, derivatives, and salts under a variety of reaction conditions.
Lithistida sponges produce a diverse array of structurally complex compounds such as microsclerodermins with potent and unique biological activities. Potentially bioactive molecules isolated from living organisms such as marine life are commonly recognized as being more effective than those obtained through combinatorial synthetic chemistry. With synthetic libraries, there are a limited number of synthetic reactions resulting in a lack of structurally diversity and exploration of the biological space. Marine natural products are often enzymatically engineered and biologically validated and may represent a higher quality product. Recent technical advances in the synthesis of these compounds have furthered their development into promising therapeutic agents. The marine-derived microsclerodermin F technology has potent anti-proliferative activity against tumor cells, as it completely inhibits mitosis at low Ic50 concentrations and shows pronounced changes in normal microtubule arrangement in A549 lung cancer and Hct-116 colon cancer cells. Microsclerodermin F has a highly unusual amino acid sequence and probable unique mechanism of action making it highly useful in the treatment of Taxane or drug-resistant tumors. It also belongs to the class of cyclic peptides, which have immense therapeutic utility due to their intrinsic, enhanced protein binding affinity and metabolic stability.
Many marine-derived compounds such as microslerodermin F were discovered over a decade ago, however their low recovery from sponges limited their development. Recent technical advances in the synthesis of these compounds have furthered their development into promising therapeutic agents. This technology has tremendous applicability, as it can be used to treat a variety of solid tumors and leukemia and also can cross the blood-brain barrier to treat CNS tumors. Similar to other anti-tumor marine-sponge derived compounds, microsclerodermin F can be used individually or in combination with lower doses of other standard chemotherapy regimes. It has multifaceted biologically activity, as it also can inhibit the growth of cells caused by autoimmune and inflammatory diseases. The proliferative nature of the immune response is generally controlled with immunosuppressive drugs. An alternative method of treatment such as microsclerodermin F may allow for cell growth control without the side-effects associated with a compromised immune system. Treating a variety of conditions with one class of compounds represents a huge cost savings in clinical development. Lastly, since microsclerodermins also affectively absorb UV rays, they can be used industrially as ultraviolet screeners in the plastics.
A patent has been issued for the Microsclerodermins technology. The inventors at the Harbor Branch Oceanographic Institution in Fort Pierce, Florida are looking for a partner for further development and commercialization of this technology through a license.
U.S. Patent 6,384,187 B1
Amy Wright, Ph.D. (UC, Riverside) has been working in the field of Marine Natural Products Chemistry for over 24 years. Her primary research interests focus on the purification and structure identification of naturally occurring compounds, which may have utility in treating cancer. Much of the research focuses on the investigation of deep-sea invertebrates collected using the Johnson-Sea-Link human- occupied submersibles. She has over 150 Peer Reviewed publications. Her past partnerships with large and small biotechs, Sanford Burnham, Moffitt Cancer Center, with funding from NIAID, MIGMS, MCCAM, & NOAA. Through her research, she has access to a vast (5,000+) natural marine compounds library http://dorsrv1.fau.edu/CEBMB/Libraries.aspx. Dr. Shirley Pomponi, Ph.D is Research Professor and Executive Director of the NOAA Cooperative Institute for Ocean Exploration, Research, and Technology at Harbor Branch Oceanographic Institute, Florida Atlantic University, in Fort Pierce, Florida. She received her Ph.D. in Biological Oceanography from the University of Miami. Her research focuses on marine biotechnology, in general, and sponge systematics, cell and molecular biology, in particular. She has authored or co-authored more than 100 peer-reviewed scientific publications and is co-inventor on several patents. a Research Professor at Florida Atlantic University’s Harbor Branch in Marine Biomedical and Biotech Research. Dr. Ross E. Longley, Ph.D. is an Associate Professor of Microbiology and Immunology at Lake Erie College of Osteopathic Medicine in Erie, Pennsylvania. He has authored over 37 peer-reviewed publications. Dr. Richard Isbrucker, Ph.D is a Senior Research Scientist at the Center for Biologics Research Health Canada. He has authored over 15 peer-reviewed publications.
Oncology, drug discovery, natural marine products, immunology
Novel anti-inflammatory compounds derived from extracts of marine sponges.
Inflammation and its associated pain continue to affect millions of humans and animals. New therapies are needed that are effective and have low toxicity.
Assays of new compositions of biologically active bis-heterocycles showed significant reduction in inflammation as measured in the mouse ear edema test. This proven anti-inflammatory activity offers a novel use for these bis-indoles. Surprisingly, Soritin A shows strong activity against both immunogenic and neurogenic inflammation, which is an unexpected bonus.
Three compounds are disclosed in this patent: Soritin A, HB-238; Bis(3,3’indolyl)methane, HB-236; and 2-Bis(3,3’ indolyl)acetaldehyde, HB-237, all of which were derived from marine sponges. Soritin A was tested against hydrocortisone, indomethacin, manoalide, and topsentin in the topical inhibition of phorbol myristate acetate (PMA) induced mouse ear edema. Additionally, soritin A and its analogs were tested against resiniferatoxin (RTX) induced ear edema in the mouse and showed impressive results.
Marine sponges are a ready-made source of innumerable biologically active compounds that may have commercial applications. These bis-indoles, derived from marine sponges, have been isolated, characterized, and synthesized. As demonstrated by the mouse ear edema assays, soritin A is especially intriguing as a highly effective anti-inflammatory compound. The compounds can be used in various dosage forms and administered via many routes including liposome technology, slow release capsules, implantable pump, or biodegradable carrier. The flexibility of dosage forms and routes of administration offer a distinct advantage over many marketed anti-inflammatories.
These novel compounds also demonstrate the ability to block both immunogenic and neurogenic inflammation. Asthma, allergies, rheumatoid arthritis, and diseases that cause joint inflammation are all examples of immunogenic inflammatory conditions that are in need of promising new pharmaceutical compositions. Neurogenic inflammation is linked to conditions such spinal cord injury, diabetic side effects, and even cardiovascular diseases. Soritin A may also have therapeutic potential in wound healing, giving it a double advantage in cases where both wounds and inflammation are present.
The commercial opportunities are vast for therapeutic substances that can reduce inflammation in a clinically meaningful way. Inflammation is part of the equation in conditions such as migraine, arthritis, burns, chronic pain, cardiovascular diseases, certain cancers, and many more. Conventional anti-inflammatories can cause serious adverse effects, including upper gastrointestinal bleeding. There is a market for novel anti-inflammatories that are effective in small doses, and offer an acceptable safety profile.
U.S. Patent 6,323,233 November 27, 2001 (incorporating U.S. Patent 4,866,084).
U.S. Patent 4,970,226; U.S. Patent 5,290,777 and U.S. Patent 5,464,835.
Amy E. Wright Ph.D. Director, Research Professor, Harbor Branch Oceanographic at Florida Atlantic University. Currently on the faculty of the Medical University of South Carolina, in the Marine Biomedicine and Environmental Sciences Department, Dr. Wright has conducted research in the field of natural products chemistry. Her research focuses on the discovery of compounds with utility in the treatment of cancer and infectious disease. She has authored approximately 60 publications and 34 patents.
Ralph-Heiko Mattern Ph.D., Formerly with Integra Neurosciences, San Diego, California has authored seven patents and 43 publications. He has worked on development of collagen based medical devices such as artificial skin and nerve guides. He is currently an independent consultant in the fields of medical devices, collagen products, and peptide formulation.
Robert S. Jacobs Ph.D., Professor Emeritus of Pharmacology, Department of Ecology, Evolution and Marine Biology, University of California, Santa Barbara, California. His research interests concern the cellular and molecular mechanism of action of marine natural products and toxins. He has authored approximately 89 publications and 23 patents.
Anti-Inflammatory Agents; Drug discovery
Novel organic compounds derived from extracts of marine soft corals that show biological activity in vitro.
Cancer, autoimmune conditions, and inflammatory diseases continue to affect millions of humans and animals. New therapies are needed to combat cancers, organ rejection, diabetes, lupus, meningitis, Parkinson’s disease, Alzheimer’s disease, ALS, and more.
Assays of two new linderazulene compounds showed inhibition of undesirable cell proliferation. Cell proliferation associated with autoimmune disorders, inflammation, tumors, and cancer are included in the claims by the inventors.
11-carbomethoxylinderazulene (I) and 11-formylinderazulene (II) were extracted from a soft coral found off the northwest coast of Curacao, using the Harbor Branch Oceanographic Institution’s Johnson-Sea-Link research submersible to gather samples. Samples were purified and concentrated using common procedures. Human pancreatic cells (PANC-1) and murine leukemia cells (P388) were used to test the anti-proliferative effects of the linderazulenes. Results were obtained by spectrophotometry. The mechanism of action was not investigated.
The linderazulenes claimed are novel compositions that are useful for an array of disorders and diseases, including cancers. Analogs and salts are also included in the patent. With the possibility of therapeutic effectiveness in more than one disease, the odds of producing a successful pharmaceutical are increased. The compounds can be formulated according to common methods. Only four papers in the literature discuss linderazulenes:
1: Chen M, Han L, Wang Y, Zhang XL, Wang CY. A new sesquiterpene from the Hainan gorgonian Menella kanisa Grassoff. Nat Prod Res. 2014;28(15):1147-51. doi:10.1080/14786419.2014.918122.
2: Pénez N, Culioli G, Pérez T, Briand JF, Thomas OP, Blache Y. Antifouling properties of simple indole and purine alkaloids from the Mediterranean gorgonian Paramuricea clavata. J Nat Prod. 2011 Oct 28;74(10):2304-8. doi:10.1021/np200537v.
3: Reddy NS, Reed JK, Longley RE, Wright AE. Two new cytotoxic linderazulenes from a deep-sea gorgonian of the genus Paramuricea. J Nat Prod. 2005 Feb;68(2):248-50.
4: Sakemi S, Higa T. 2,3-Dihydrolinderazulene, a new bioactive azulene pigment from the gorgonian Acalycigorgia sp. Experientia. 1987 Jun 15;43(6):624-5.
The unmet need for effective treatments for cancers and tumors, autoimmune disorders, and inflammation is huge and continues to grow with the population. In 2012, autoimmune diseases affected approximately 23.5 M people in the U.S. according to the NIH. New cases of cancer in the U.S. were over 1.6M in 2014 with 40% of the population predicted to be diagnosed with cancer at some point in the life. Inflammatory diseases cover the range body systems, from digestive to connective tissue to glandular.
U.S. Patent 6,852,754 Issued February 8, 2005.
Amy E. Wright, Ph.D. Director, Research Professor, Harbor Branch Oceanographic at Florida Atlantic University. Currently on the faculty of the Medical University of South Carolina in the Marine Biomedicine and Environmental Sciences department. Dr. Wright has conducted research in the field of natural products chemistry. Her research focuses on the discovery of compounds with utility in the treatment of cancer and infectious disease. She has published approximately 60 articles and is an author on 34 patents.
Ross E. Longley, Ph.D. NPDDL Laboratory Director; Coordinator of Research Programs; Associate Professor of Microbiology and Immunology, Lake Erie College of Osteopathic Medicine-Bradenton FL. From 1984 to 1987, Dr. Longley was on the faculty at the University of Central Florida, Department of Biology, as an Assistant Professor to both undergraduate and graduate students of immunology and cancer biology. In 1987, he took the Group Leader position at the not-for-profit research organization Harbor Branch Oceanographic Institution. Dr. Longley’s team designed and implemented new screening assays for drug discovery and mechanism of action work in the Immunology and Cancer Research Program. For the next 15 years, under his direction, his laboratory discovered potential anti-cancer agents in marine natural products. In 1992 and again in 1997, he was awarded grants from the National Cancer Institute for the detection of anti-cancer agents found in marine organisms. Thanks to Dr. Longley’s research, the compound discodermolide was discovered and subsequently licensed in 1998 by Novartis pharmaceutical company. Discodermolide is presently in clinical trial as a new anti-cancer agent. After 15 years with Harbor Branch, Dr. Longley joined Taxolog, Inc., in May 2002.Dr. Longley’s research (2007) included taxane drug discovery, assay development, molecular and cellular immunology, tumor biology, flow cytometric methods for analysis of apoptosis and cell cycle-mediated events, mechanism of action studies of taxane derivatives and confocal microscopy methodology for mechanism of action studies.
Srinivasa Reddy Natala Ph.D. has been an author on 7 issued patents, six of which are assigned to Takeda. He was active in the development of TAK960, an anticancer agent from Takeda that is in Phase I trials (2013).
John K. Reed Ph.D. is a Senior Scientist with the Division of Biomedical Marine Research at Harbor Branch Oceanographic Institution. On that website he states: Our work at the Division of Biomedical Marine Research has led to the discovery of many new chemical compounds that may have potential in the treatment of various human diseases. One is now in clinical trials for the treatment of breast cancer. After 15 years of research, we are very hopeful that this will provide a new cure for breast cancer. We recently received a $1 million grant to discover a new treatment for pancreatic cancer. During this NOAA mission to the Gulf of Mexico, we will collect new species and certainly hope to discover novel chemicals that could provide that cure.
Oncology, Drug discovery
Three similar compounds isolated from marine sponges of the family Desmacididae that demonstrate anti-proliferative activity in vitro.
Cancer remains a major cause of illness, disability, and death. According to the World Health Organization, cancer is a leading cause of death worldwide, accounting for 8.2 million deaths in 2012.
Discorhabdin S, T, and U and their analogs have shown activity against cancer cell lines in vitro.
These compounds have a molecular structure that is distinct from other discorhabdins. They differ from each other only in the degree of saturation of the double bonds in the heteroaromatic rings. The inventors assessed anti-proliferative activity in human adenocarcinoma (A549), human pancreatic (PANC-1), and murine leukemia (P388) cell lines. Cells were cultured and then incubated with various concentrations of the test compounds. Results, determined by spectrophotometry, showed that these discorhabdins were effective in inhibiting the growth of cancer cells. The mechanism of action is unknown.
Only two published papers mention discorhabdin S, T, or U. One is authored by Gunsekera et al., and the other is below:
Bioorg Med Chem Lett. 2006 Apr 1;16(7):1944-6. Epub 2006 Jan 24.Semi-synthetic preparation of the rare, cytotoxic, deep-sea sourced sponge metabolites discorhabdins P and U.
Grkovic T, Kaur B, Webb VL, Copp BR.
Semi-synthetic routes to the enzyme inhibitory and potently anti-proliferative marine natural products discorhabdins P and U were developed by one-step methylation reactions of discorhabdins C and B, respectively. Two novel semi-synthetic derivatives of discorhabdin U were also prepared, one of which (6) exhibited significant anti-proliferative activity.
There remains a need for new and effective anticancer agents for humans and animals. Natural sources of biologically active compounds are yielding a growing number of effective therapeutic agents for various diseases. Using marine sponges as a source for new anticancer and antitumor agents expands the arsenal of available, effective, and novel therapeutic agents.
More effective antitumor and anticancer agents are needed. Only 66% of people with cancer will survive for at least 5 years, according to the National Cancer Institute so there is a great need for new anticancer agents. Although there may be some common characteristics among cancers and tumors, different types of tumors or cancers respond differently to the same therapy. An array of therapeutic compounds is needed in order to accommodate specific characteristics of particular tumor types or cancers. There is room in the market for new anti-proliferative compounds.
U.S. Patent 6,835,736 Issued Dec. 28, 2004.
Sarath P. Gunasekera , Ph.D. has been publishing in the field of natural products since 1973. Dr. Gunasekera is a scientist with the Harbor Branch Oceanographic’s Division of Biomedical Marine Research. His research interests include marine natural products chemistry with an emphasis on biologically active compounds having potential medicinal value. Current research focuses on the discovery of biologically active compounds from sponges and deep water microorganisms using enzymes that have potential as targets for therapeutic agents. Other interests include the chemical modification of biologically active compounds, examples: anti-cancer agent discodermolide and anti-inflammatory agents topsentins, for structure activity studies, and also, the use of high resolution NMR techniques for structure analysis. He has authored 96 publications and 21 patents.
Ross E. Longley, Ph.D. NPDDL Laboratory Director; Coordinator of Research Programs; Associate Professor of Microbiology and Immunology, Lake Erie College of Osteopathic Medicine-Bradenton FL. From 1984 to 1987, Dr. Longley was on the faculty at the University of Central Florida, Department of Biology, as an Assistant Professor to both undergraduate and graduate students of immunology and cancer biology. In 1987, he took the Group Leader position at the not-for-profit research organization Harbor Branch Oceanographic Institution. Dr. Longley’s team designed and implemented new screening assays for drug discovery and mechanism of action work in the Immunology and Cancer Research Program. For the next 15 years, under his direction, his laboratory discovered potential anti-cancer agents in marine natural products. In 1992 and again in 1997, he was awarded grants from the National Cancer Institute for the detection of anti-cancer agents found in marine organisms. Thanks to Dr. Longley’s research, the compound discodermolide was discovered and subsequently licensed in 1998 by Novartis pharmaceutical company. Discodermolide is presently in clinical trial as a new anti-cancer agent. After 15 years with Harbor Branch, Dr. Longley joined Taxolog, Inc., in May 2002.Dr. Longley’s research (2007) included taxane drug discovery, assay development, molecular and cellular immunology, tumor biology, flow cytometric methods for analysis of apoptosis and cell cycle-mediated events, mechanism of action studies of taxane derivatives and confocal microscopy methodology for mechanism of action studies.
Shirley A. Pomponi, Ph.D. In addition to directing the Division of Biomedical Marine Research, Dr. Pomponi leads the Marine Invertebrate Cell Culture Program. A major emphasis of her research is on the development of methods for sustainable use of marine resources for drug discovery and development. Research is focused on establishing cell lines of marine sponges that can be used as models to study production of sponge-derived bioactive metabolites and the factors which control expression of production. Dr. Pomponi discovered a chemical that can kill cancer cells, called discodermolide.
Amy Wright, Ph.D. Director, Research Professor, Harbor Branch Oceanographic at Florida Atlantic University. Currently on the faculty of the Medical University of South Carolina in the Marine Biomedicine and Environmental Sciences department. Dr. Wright has conducted research in the field of natural products chemistry. Her research focuses on the discovery of compounds with utility in the treatment of cancer and infectious disease. She has published approximately 60 articles and is an author on 34 patents.
Oncology, Drug discovery
Lasonides C, D, E, F - active marine-derived macrolide compounds - show anti-cell proliferative activities in vitro that could be use primarily in the treatment of cancer also in the treatment of multi-drug resistant cancer cells, secondarily in the treatment of fungal infections preferably in mammal then for the control of fungi growth in spoilage of food, in cosmetic and other consumer items.
1/ In 2014, about 1,665,540 new cancer cases are expected to be diagnosed in the U.S. and about 585,720 are expected to die of cancer, almost 1,600 people per day. Cancer is the second most common cause of death in the US. Cancer is characterized by an accelerated and uncontrolled multiplication of a set of aberrant cells, which lose their apoptotic ability. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling the growth of, for example, tumors, new methods and antitumor chemical compositions are needed, as well as in multi-drug resistance (MDR).
2/ Infestations in humans, animals and plants have increased, with many having lethal consequences. There are growing needs amongst others in controlling fungi. Fungi are highly resistant microbiological eukaryotic microorganisms. On the one hand, increased use of antibiotics and immunosuppressive drugs are major factors contributing to higher frequency of fungal infections in immunocompromised patients. One the other hand, chemical fungicides have raised environmental and safety concerns (oncogenic nature, teratogenic effects on human and soil pollution) and the regulation of food safety has become more stringent for avoiding food poisoning. While certain methods and chemical compositions have been developed that aid in inhibiting or controlling the growth of fungi, new methods and new effective antifungal compounds or compositions are needed.
The technology is a bioassay-guided fractionation of an extract that led to the isolation of four structurally different compounds, lasonolides C, D, E and F from an ocean sponge, Forcepia triabilis. These compounds are biologically active macrolides with anti-cell proliferation activities that show utility in inhibiting cancer cells and fungal growth.
The inventors have shown that lasonolides C, D, E and F have potent anti-tumor activities. It extends to the compositions with these compounds, their enantiomeric forms in excess, their analogues and their derived-salts. Furthermore, lasonolide compounds C and F have potent anti-fungal activities. Lasonolides C, D, E and F are useful for inhibiting pathological cellular proliferation in primary end-use of the treatment of cancer as well as in the treatment of multi-drug resistant cancer cells, secondary in the treatment of fungal infections, particularly lasonolides C and F, preferably in mammal then for the control of fungi growth in spoilage of food, in cosmetic and other consumer items.
As example, lasonolides C, D, E have cytotoxic activities on tumoral cells candidates (A549 human lung adenocarcinoma, PANC-1 human pancreatic cancer and NCI-ADR RES ) with IC50 values from 0.12µM to >8µM). Also, against a fungi candidate, Candida albicans, lasonolides C and F reach their minimum inhibitory concentration (MIC) respectively at 5µg/ml and 50µg/ml.
This is a sustaining technology that brings great value by offering a natural alternative for the control of fungi and for the treatment of the multi-drug resistance (MDR) or multidrug resistance-associated protein (MRP) cases.
The primary field of use of the technology is the treatment of cancer, as well as the treatment of multi-drug resistant cancer cells. The expansion of new drugs in oncology represents one of the most promising objectives of the pharmaceutical industry. Indeed, across 2013, 15 new molecular entities were approved by the FDA; out of which seven were for oncology. Currently targeted therapies dominate the oncology pipeline, followed by chemotherapy. The market landscape is highly competitive; however, the need for novel anti-tumor compounds is high.
The secondary field of use is in the development of antifungal products: - Preferably in mammal. The U.S. human antifungal therapeutics market reached nearly $4.9 billion in 2013. It is projected to grow to $5.5 billion in 2018; - Then for the control of fungi growth in spoilage of food, in cosmetic and other consumer items. The demand particularly for food safety products in the U.S. is forecast to increase of 7.3 percent annually to $4.5 billion in 2016.
U.S. Patent US 7,521,474 B2 Biologically Active Lasonolide Compounds Issued on April 21st, 2009.
Amy E. Wright, Ph.D. (UC, Riverside) is Research Professor and Director of the Center for Marine Biomedical and Biotechnology Research at Harbor Branch Oceanographic Institute, Florida Atlantic University. She has conducted research, for the past 25 years, in the field of natural products chemistry. Her primary research interests focus on the purification and structure identification of naturally occurring compounds, which may have utility in treating cancer. Over the course of her career, her research group has identified over 100 different marine natural products with biological activity. One compound she identified early in her career has been approved in Europe for the treatment of soft tissue sarcoma.
Shirley A. Pomponi, Ph.D. (University of Miami) is Research Professor and Executive Director of the NOAA Cooperative Institute for Ocean Exploration, Research, and Technology at Harbor Branch Oceanographic Institute, Florida Atlantic University. Her research focuses on marine biotechnology, in general, and sponge systematics, cell and molecular biology, in particular.
Peter J. McCarthy, Ph.D. (University of Kent, Canterbury, UK) is Research Professor at the Center for Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute, Florida Atlantic University. His research focuses on the discovery of novel natural products and enzymes produced by heterotrophic marine-derived microorganisms.
Ross E. Longleya, Ph.D. (University of Oklahoma) is Senior Vice President of Preclinical Research and Development of Taxolog, Inc. He has been Group Leader for Harbor Branch Oceanographic Institution since 1987. His team designed and implemented new screening assays for drug discovery and mechanism of action work in the Immunology and Cancer Research Program. For the next 15 years, under his direction, his laboratory discovered potential anti-cancer agents in marine natural products.
Ying Chen, M.S. (Fudan of Science and Technology and Academia Sinica, China) is Senior Analytical Chemist at Boston Analytical Inc and was Research Associate for Ocean Exploration, Research, and Technology at Harbor Branch Oceanographic Institute, Florida Atlantic University.
Oncology, Fungal infection, Food microbiology
Compounds derived from marine and natural products have potent anti-malarial activity and include cembranoid-type diterpenes, microsclerodermins, dercitamides, and bis-indoles. These agents can be used to treat or prevent malarial infection.
Malaria, an infectious disease caused by Plasmodium parasite transmission from mosquitoes, is one of the most severe public health problems worldwide. It is the leading cause of death and disease in many developing countries, with young children and pregnant women most commonly affected. Over 3.4 billion people (half of the world’s population) live in areas at risk for malaria transmission (106 countries and territories). An estimated 207 million people contracted malaria in 2012, resulting in 627,000 reported deaths of which 90% were in Sub-Saharan Africa and 77% were among children under 5. It imposes a substantial economic burden to individuals and governments, with costs estimated at more than $12 billion per year, not including the total loss in economic growth. As a result of the emergence of a combination of new interventions including reliable diagnostic tests and effective drugs, the number of new cases has declined 25% with a 42% reduction in deaths. However, current tools and treatments are insufficient to eliminate malaria, as more drug resistant strains have developed and continued to spread and a vaccine is still unavailable. Therefore, there is a significant need for new drugs and strategies to treat and prevent malarial infection.
The inventors have isolated four novel classes of anti-malarial compounds from marine and natural products that have potent, and selective anti-malarial activity and include cembranoid-type diterpenes, microsclerodermins, dercitamides, and bis-indoles. Since these compounds have unique structures, they likely act upon novel cellular targets and may alleviate the drug resistance problem of current treatments. This technology proposes methods for treating and/or preventing malarial infection using these new agents. The compositions can be administered individually or in combination with at least one other agent including a stabilizing compound or other therapeutic agent currently used for the treatment/prevention of malaria.
Living organisms such as marine life are a recognized source of potentially bioactive molecules, which a commonly more effective than those obtained through combinatorial synthetic chemistry. Although synthetic libraries are straightforward to assemble, there are a limited number of synthetic reactions and structurally diverse building blocks, implicating a lack of structurally diversity and exploration of the biological space. Marine natural products are also enzymatically engineered and biologically validated, representing a higher quality product. Not surprisingly, the most significant recent advancements in malaria have been made through natural leads. This technology is a product derived from natural marine products and shows highly selective, potent activity against chloroquine resistant strains of P. falciparum. The inventors anticipate the technology to act on novel cellular targets, which is highly advantageous since resistant malaria strains are becoming more prevalent and continue to multiply despite being treated with anti-malarial compounds. It is also expected that the next significant advancement in anti-malarial drugs will not be reached through the discovery of a single, potent compound, but rather through the introduction of an innovative drug to be used in a combined therapy, preferably composed of molecules acting at different stages of the microorganisms’ life cycle. The proposed technology is highly advantageous since its activity can be retained and enhanced through combinatorial therapy and its stability can be increased with a stabilizing compound.
Due to widespread resistance to commonly used anti-malarial oral drugs such as chloroquine and anti-folates, in 2006, an endoperoxide sesquiterpene from Artemisia annua (Chinese herbal remedy) called artemisinin, became the frontline therapy for treatment of malaria. Artemisinin and its derivatives are currently the only viable, cheap options for treatment. However, in 2014, the WHO declared rapid withdrawal of artemisinin monotherapy due to the emergence and spread of artemisinin-resistant strains. The continuous appearance of drug-resistant P. falciparum strains has made the chemotherapeutic management of malaria increasingly problematic in virtually all malaria-plagued regions of the world. Compounded by the absence of a vaccine for protection, this recent epidemic of resistance has underscored the importance of developing new drugs and new drug targets to treat the disease. As a result of artemisinin resistance, an artemisinin combination therapy (ACT) is now the standard of treatment worldwide. Intense efforts are currently being made to extend the life of existing drugs while major drug discovery initiatives are underway. The current technology certainly has a well-defined place in the market as a novel treatment with novel targets, which can be effectively developed into a combination therapy.
• Screening, isolation, and identification of marine compounds with anti-malarial activity • Anti-plasmoidal activity tested in P. falciparum choloroquine-resistant Dd2 cells
• Cytotoxicity tested in NIH 3T3 cells (mouse embryonic fibroblasts) to verify selectivity • Pharmaceutical compositions comprising one or more anti-malarial agents have been
identified (with and without carriers) • Strategy for determining the effective therapeutic dose in place
A patent has been issued for the anti-malarial compounds technology. The University of Central Florida and Florida Atlantic University are looking for a partner for further development and commercialization of this technology through a license. U.S. Patent Publication: 20140200226A1 Publication Date: July 17, 2014
Dr. Debopam Chakrabarti, Ph.D., is a Professor at Central Florida’s Burnett School of Biomedical Sciences. With 25 years of experience in molecular parasitology, target validation, and anti-infective drug discovery, he has authored over 86 peer-reviewed publications. Amy Wright, Ph.D. (UC, Riverside) has been working in the field of Marine Natural Products Chemistry for over 24 years. Her primary research interests focus on the purification and structure identification of naturally occurring compounds, which may have utility in treating cancer. Much of the research focuses on the investigation of deep-sea invertebrates collected using the Johnson-Sea-Link human- occupied submersibles. She has over 150 Peer Reviewed publications. Her past partnerships with large and small biotechs, Sanford Burnham, Moffitt Cancer Center, with funding from NIAID, MIGMS, MCCAM, & NOAA. Through her research, she has access to a vast (5,000+) natural marine compounds library http://dorsrv1.fau.edu/CEBMB/Libraries.aspx.
Medical/molecular parasitology, infectious disease, drug discovery