Translating Natural Products into Drugs for Alzheimer's and Neurodegenerative Disease
Posted July 03, 2013
Alzheimer's disease (AD) is a terminal illness causing dementia and progressive neurological deterioration, and its prevalence increases dramatically as people age. In 2012 it was the sixth most frequent cause of death in the U.S., and the increasing death rate is expected to continue rising as the population ages. The CDC reports that the associated cost of health care was $200 billion in 2012 and is predicted to grow to $1.1 trillion by 2050. There is no cure: available drugs can alleviate some symptoms and slow progression, but none target the—still unclear—molecular mechanisms underlying the disease.
On May 6, 2013, the Academy's Brain Dysfunction Discussion Group, partnering with the Alzheimer's Drug Discovery Foundation, presented Translating Natural Products into Drugs for Alzheimer's and Neurodegenerative Disease. The symposium explored efforts to derive drugs from natural products, highlighting case studies of compounds at various stages of development for the treatment of AD and neurodegeneration.
Howard Fillit from the Alzheimer's Drug Discovery Foundation set the stage by reviewing the impact of Alzheimer's on public health, calling the disease an epidemic. He also described the opportunities for drug development from natural products. Despite a trend toward using synthetic chemical libraries for drug discovery, in the past decade more than a third of all approved drugs with a novel molecular mechanism of action have come from natural products.
David J. Newman from the National Cancer Institute, Grant J. Carr from AMRI, and Frank E. Koehn from Pfizer reviewed the advantages and challenges of developing drugs from natural products. Koehn began by defining natural products as "small molecules produced by organisms through secondary metabolism for biological purposes." This definition underscores a key advantage of using natural products as a starting point for drug discovery: natural selection has optimized many of them to bind to specific targets, creating a bias towards biologically relevant compounds that is absent in synthetic libraries. As many as half of all drugs are derived from natural products, suggesting they are a rich source for drug-discovery research.
While natural products can be useful leads for new drugs, finding and collecting enough material to test can be a challenge. This process can be expensive and haphazard, involving anything from diving under the Antarctic ice to venturing into a mangrove swamp. Unlike an ordered synthetic chemical library, the starting point is an extract—a mixed bag of unknown constituents. If this extract has any therapeutic activity, the active compounds must be purified. As the speakers and Q&A sessions highlighted, these challenges make natural product screening a good candidate for precompetitive collaborations that spread the cost among several interested pharmaceutical companies. Another challenge is that the compounds can have complicated structures that are difficult to synthesize traditionally, but both Carr and Koehn demonstrated how microbial biosynthesis can be optimized to overcome this problem.
The cause of AD in most patients is unknown. What is clear is that parts of the brain become crowded with amyloid plaques and neurofibrillary tangles, and synaptic communication based on the neurotransmitter acetylcholine is deficient. In a minority of cases the disease is heritable, and these patients have mutations in the protein constituents of plaques (amyloid-β, Aβ) or tangles (hyperphosphorylated tau), or in the pathways that process these constituents. Introducing these mutations into mice leads to symptoms that resemble AD in humans, making these animals valuable models of the disease. As Aβ and hyperphosphorylated tau proteins accumulate in plaques and tangles, the brain degenerates; this correlation is suspected to reflect a causal relationship. The search is on for compounds that prevent or shrink plaques and tangles or counteract their effects.
Bonnie M. Davis of Synaptec began the case study presentation by reviewing her work to spearhead galantamine (a compound from the snowdrop plant Galanthus nivalis) as a treatment for mild to moderate AD. Galantamine acts in two ways: it inhibits the enzyme that degrades acetylcholine and it promotes target neurons' responses to the neurotransmitter by binding to membrane receptors. This binding makes the smaller amount of acetylcholine in the brains of AD patients more effective, alleviating some of the symptoms of the disease and reducing mortality.
Strategies targeting tau attempt to reduce the number of neurofibrillary tangles, which contain hyperphosphorylated tau, or to compensate for what tau normally does but cannot do when it is ensnared in those tangles. Chad Dickey from the University of South Florida presented evidence that myricanol, a compound found in bayberry extracts (from the Myrica cerifera plant), can reduce the level of tau in cells. The hope is that this work will create a starting point to develop—by further chemical modification—drugs that only target the aberrant forms of the protein that are present in neurofibrillary tangles.
Gabriela Chiosis from Memorial Sloan-Kettering Cancer Center described another strategy. Rather than aiming directly at hyperphosphorylated tau, she is attempting to enhance cellular "housekeeping" functions that can eliminate neurofibrillary tangles in neurons. Geldanamycin, found in the bacteria Streptomyces hygroscopicus, inhibits a protein called Hsp90. This protein both turns off a cellular program that can clear tangles and seems to stabilize hyperphosphorylated tau; inhibiting Hsp90 with geldanamycin increases the clean-up of tangles and destabilizes the aberrant form of tau. But geldanamycin will never be a drug: it is poorly soluble, toxic, and not brain permeable. Chiosis has developed new compounds that inhibit Hsp90 but avoid these problems. Experiments in a mouse model of AD show promising results: good brain permeability, no toxicity, less hyperphosphorylated tau, and improved memory.
Kurt R. Brunden from the University of Pennsylvania presented an alternative drug-development model. Usually, tau binds to microtubules to stabilize them, but when tau is hyperphosphorylated (as in AD) it falls off. Under normal conditions, microtubules form rail-like structures inside neurons, serving as conduits for the transport of substances up and down the length of axons. When microtubules lose tau they break apart, making efficient transport in neurons impossible and causing axons to degenerate. Brunden's approach is to use drugs that stabilize microtubules, keeping the neuron's transport system working. Epothilone D (EpoD), a compound originally identified in the soil bacterium Sorangium cellulolus, has this effect. It can reach the brain, making it a good drug candidate. EpoD is effective for both preventing and reverting axonal degeneration and cognitive decay in mouse models of AD and is now in phase Ib clinical trials.
Salvatore Oddo from the University of Texas Health Science Center at San Antonio moved the focus of the meeting from tau to Aβ, delving into the effects of inhibiting a signaling protein called the mammalian target of rapamycin (mTOR). When mTOR is active it can induce cell growth and inhibit autophagy (a process by which cells degrade internal components). In a mouse model of the disease, Aβ accumulation leads to an increase in mTOR activity. Rapamycin, a compound originally discovered in Streptomyces hygroscopicus soil bacteria collected on Easter Island, inhibits mTOR. A mouse model of AD had less amyloid plaques and hyperphosphorylated tau in the brain after rapamycin administration, as well as improved motor activity and improved ability to learn and remember tasks. This suggests that increased activity of mTOR leads to some symptoms of AD, making this protein a potential drug target. Rapamycin is an immunosuppressant drug approved by the U.S. Food and Drug Administration (FDA), but it can have serious side effects. Nevertheless, it is possible that with an intermittent schedule these side effects could be minimized, making rapamycin a potential drug for AD.
Jerold Chun from the Scripps Research Institute shifted the discussion to multiple sclerosis (MS), an autoimmune neurodegenerative disease. Chun related the successful story of fingolimod, a lipid derived from fungal metabolites which was approved by the FDA in 2012 as the first oral treatment for relapsing forms of MS. While the drug was originally thought to act exclusively through a receptor on cells of the immune system, it also seems to have direct effects on the brain, reducing atrophy in MS patients. It is an open question whether similar drugs hold therapeutic potential for AD.
The day ended with a talk by Giulio M. Pasinetti of Mount Sinai School of Medicine. Pasinetti discussed the potential beneficial effects of polyphenolic compounds found in red wine. In mouse models of AD, consumption of moderate amounts of wine or a monomeric polyphenolic extract from the wine enhances learning and reduces Aβ. Recently, his lab has focused on 3′-O-methyl-epicatechin-5-O-β-glucuronide, which enhances neurotransmission and synaptic plasticity in brain slices from a mouse model of AD and can be readily absorbed by the brain. It is still unknown whether this is the active compound. If so, it could represent an avenue for drug development.
The meeting demonstrated the potential for developing drugs from natural products for Alzheimer's disease. While these products may be challenging to find and screen for biological activity, history suggests that valuable drug candidates may lurk in unexpected places.
Use the tab above to find multimedia from this event.
Presentations available from:
Kurt R. Brunden, PhD (University of Pennsylvania)
Grant J. Carr, DPhil (AMRI)
Gabriela Chiosis, PhD (Memorial Sloan-Kettering Cancer Center)
Jerold Chun, MD, PhD (The Scripps Research Institute)
Chad Dickey, PhD (University of South Florida)
Howard Fillit, MD (Alzheimer's Drug Discovery Foundation)
Frank E. Koehn, PhD (Pfizer)
David J. Newman, PhD (National Cancer Institute, NIH)
Salvatore Oddo, PhD (University of Texas Health Science Center)
Giulio M. Pasinetti, MD, PhD (Mount Sinai School of Medicine)
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Journal Articles and Reports
Brunden KR, Ballatore C, Lee VM, et al. Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies. Biochem Soc Trans. 2012;40(4):661-6.
Caccamo A, Magrì A, Medina DX, et al. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies. Aging Cell. 2013;12(3):370-80.
Caccamo A, Maldonado MA, Majumder S, et al. Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism. J Biol Chem. 2011;286(11):8924-32.
Centers for Disease Control and Prevention. Mortality from Alzheimer's disease in the United States: Data for 2000 and 2010. NCHS Data Brief 116. 2013.
Cohen JA, Chun J. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759-77.
Cragg GM, Newman DJ. Natural products: a continuing source of novel drug leads. Biochim Biophys Acta. 2013;1830(6):3670-95.
Engedal K, Davis B, Richarz U, et al. Two galantamine titration regimens in patients switched from donepezil. Acta Neurol Scand. 2012;126(1):37-44.
Ganesan A. The impact of natural products upon modern drug discovery. Curr Opin Chem Biol. 2008;2(3):306-17.
Ho L, Ferruzzi MG, Janle EM, et al. Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease. FASEB J. 2013;27(2):769-81.
Jones JR, Lebar MD, Jinwal UK, et al. The diarylheptanoid (+)-aR,11S-myricanol and two flavones from bayberry (Myrica cerifera) destabilize the microtubule-associated protein tau. J Nat Prod. 2011;74(1):38-44.
Luo W, Sun W, Taldone T, et al. Heat shock protein 90 in neurodegenerative diseases. Mol Neurodegener. 2010;5:24.
Majumder S, Richardson A, Strong R, Oddo S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One. 2011;6(9):e25416.
Razay G, Wilcock GK. Galantamine in Alzheimer's disease. Expert Rev Neurother. 2008;8(1):9-17.
Richarz U, Engedal K, Davis B, et al. Efficacy and tolerability of two galantamine titration regimens in patients switched from donepezil. Alzheimers Dement. 2011;7(4):S800.
Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Discov. 2011;10(7):507-19.
Wang J, Ferruzzi MG, Ho L, et al. Brain-targeted proanthocyanidin metabolites for Alzheimer's disease treatment. J Neurosci. 2012;32(15):5144-50.
Howard Fillit, MD
Howard Fillit, a geriatrician, neuroscientist, and leading expert in Alzheimer's disease, is the founding executive director of the Alzheimer's Drug Discovery Foundation (ADDF). The foundation's mission is to accelerate the discovery and development of drugs to prevent, treat, and cure Alzheimer's disease, related dementias, and cognitive aging. Fillit has had a distinguished academic medicine career at The Rockefeller University and Mount Sinai School of Medicine, where he is a clinical professor of geriatrics and medicine and a professor of neurobiology. He is the senior editor of the Textbook of Geriatric Medicine and Gerontology. Fillit was previously the corporate medical director for Medicare at New York Life, responsible for over 125 000 Medicare managed-care members in five regional markets. Fillit has received several awards and honors, including the Rita Hayworth Award for Lifetime Achievement. He also serves as a consultant to pharmaceutical and biotechnology companies, health care organizations, and philanthropies.
Jennifer Henry, PhD
The New York Academy of Sciences
Jennifer Henry is the director of Life Sciences at the New York Academy of Sciences. Henry joined the Academy in 2009, before which she was a publishing manager in the Academic Journals division at Nature Publishing Group. She also has eight years of direct editorial experience as editor of Functional Plant Biology for CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University of Melbourne, specializing in the genetic engineering of transgenic crops. As director of Life Sciences, she is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology. She also generates alliances with organizations interested in developing programmatic content.
Kurt R. Brunden, PhD
Kurt R. Brunden is the director of drug discovery and a research professor at the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania, where he oversees drug-discovery programs in the areas of Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease. Before joining CNDR, Brunden served as a vice president in two publicly-traded biotechnology companies, leading drug-discovery and development programs in Alzheimer's disease, schizophrenia, metabolic disease, inflammation, and oncology. Earlier in his career, Brunden was an NIH-funded faculty member in the Biochemistry Department at the University of Mississippi Medical Center. He holds a PhD in biochemistry from Purdue University and completed a postdoctoral fellowship at the Mayo Clinic.
Grant J. Carr, DPhil
Grant J. Carr has over 20 years experience in the biotechnology and pharmaceutical industries, contributing to the development of therapeutic-protein and small-molecule drugs and to the discovery of a number of clinical candidates. At AMRI Carr leads the company's vitrobiology/pharmacology efforts and natural product-based drug discovery. He has developed strategies for a wide range of targets and therapeutic areas including CNS, diabetes, inflammation, osteoporosis, and cardiovascular disorders. More recently, he led AMRI's efforts to discover novel antibacterial drugs to treat multi-drug resistant bacterial infections. Before joining AMRI Carr was the director of screening operations at Elitra Pharmaceuticals, where he worked on a novel platform technology for the identification of antibacterial compounds with specific mechanisms of action, utilizing hyper-sensitive cell-based assays. He also co-invented a technology to identify the mechanism of action of any antibacterial compound. Before joining Elitra, Carr founded the HTS group at Arris.
Gabriela Chiosis, PhD
Gabriela Chiosis is a principal investigator and associate member in the Program in Molecular Pharmacology and Chemistry at Sloan-Kettering Institute and an associate attending in the Department of Medicine at Memorial Hospital for Cancer & Allied Diseases. She is also a faculty in several biomedical graduate programs, including at the Weill Graduate School of Medical Sciences at Cornell University, Sloan-Kettering Institute for Cancer Center at Cornell University and The Rockefeller University, and the Gerstner Sloan-Kettering Graduate School. Her laboratory investigates modulating molecular chaperones in disease treatment. It has developed pharmacological tools instrumental in defining the roles of Hsp90 in regulating the stability and function of aberrant protein driving the neurodegenerative phenotype in tauopathies. Hsp90 inhibitors discovered by the lab are platforms for the development of several purine-scaffold Hsp90 inhibitors currently in clinical evaluation in patients with advanced cancers. Chiosis holds a PhD from Columbia University.
Jerold Chun, MD, PhD
Jerold Chun is a professor in the Molecular and Cellular Neuroscience Department at Dorris Neuroscience Center at The Scripps Research Institute (TSRI) and an adjunct professor of pharmacology and neuroscience at the University of California, San Diego (UCSD) School of Medicine. His laboratory identified the first lysophospholipid receptor and has contributed to understanding the roles of this receptor family—which includes receptors for sphingosine 1-phosphate (S1P), the target for the Multiple Sclerosis drug fingolimod—in normal and diseased states. He holds both an MD and a PhD in neuroscience from Stanford University School of Medicine and complete postdoctoral work at the Whitehead Institute at MIT. He held positions as a professor at UCSD School of Medicine and as senior director and department head of molecular neuroscience at Merck before joining TSRI.
Bonnie M. Davis, MD
Bonnie M. Davis is the inventor of the use of galantamine for Alzheimer's disease and related dementias. Her patents have been licensed to Ciba-Geigy (now Novartis), Hoechst Roussel (now Sanofi-Aventis), Johnson & Johnson, and Shire. She is the founder and CEO of Synaptec, which is currently developing compounds as positive allosteric modulators of nicotinic receptors. Davis holds an MD from the Mount Sinai School of Medicine and trained in internal medicine at Kaiser Hospital in Santa Clara. She performed early studies in insulin resistance as a fellow in endocrinology and metabolism at Stanford Medical Center. As a faculty member at Mount Sinai she served as medical director of the Psychiatric Clinical Research Center and conducted endocrine studies in Alzheimer's disease and schizophrenia. She was elected to the Board of Trustees of the Mount Sinai Medical Center in 2007, where she chairs the committee on technology transfer.
Chad Dickey, PhD
Chad Dickey joined the faculty at the Byrd Alzheimer's Institute at the University of South Florida in 2008. He holds a PhD from the university and completed postdoctoral training at the Mayo Clinic under the direction of Michael Hutton, an expert in Alzheimer's disease genetics. He is the recipient of a New Investigator Award from the Alzheimer's Association and a Rosalinde and Arthur Gilbert Foundation/AFAR New Investigator Award in Alzheimer's disease. Dickey has conducted two research projects for the Society for Progressive Supranuclear Palsy to study the mechanisms behind this particular form of hereditary dementia. He is currently funded through the NIH, the VHA, AHAF, and AFAR for his research into therapeutic development for and molecular mechanisms of Alzheimer's disease and tauopathies.
Frank E. Koehn, PhD
Frank E. Koehn did his PhD research on marine red tide neurotoxins at the University of Wisconsin–Madison. After postdoctoral work in natural products at the University of Pennsylvania, he joined the Harbor Branch Oceanographic Institution in Fort Pierce, Florida, where he spent the next decade studying biologically active marine natural products. In 1994 he joined Lederle Laboratories, which subsequently became Wyeth Research. In 2010 he joined Pfizer as a research fellow. His laboratory is focused on the application of natural products in new disease therapies.
David J. Newman, PhD
David J. Newman is president of the American Society of Pharmacognosy for 2012–2013 and chief of the Natural Products Branch (NPB) in the Developmental Therapeutics Program at the National Cancer Institute. He holds a DPhil for work in microbial chemistry from the University of Sussex. He completed a postdoctoral fellowship in the Biochemistry Department at the University of Georgia and then joined SK&F as a biological chemist. He later completed an MS in information science at Drexel University. After working in marine and microbial discovery programs at various companies he joined the NPB, with responsibilities for marine and microbial collection programs. He received the NIH Award of Merit in 2003 for the development of microbial and marine drug candidates at NCI. He was appointed chief of NPB in 2006. His research interests are in natural product structures as drugs and leads thereto.
Salvatore Oddo, PhD
Salvatore Oddo received his graduate degree in the neurobiology of learning and memory from the University of California, Irvine. Oddo's research focuses on understanding the molecular mechanisms underlying memory deficits in Alzheimer's disease. Using animal models, he showed that dysfunction signaling transduction pathways that are critical for learning and memory play a pivotal role in the cognitive decline associated with Alzheimer's disease. Currently, he is the principal investigator of a grant from the National Institutes of Health focused on elucidating the role of the mammalian target of rapamycin on the pathogenesis of Alzheimer's disease. Oddo has published more than 60 research articles in international peer-reviewed journals. He has received several national and international awards in recognition of his contribution to the aging and Alzheimer's disease fields.
Giulio M. Pasinetti, MD, PhD
Giulio M. Pasinetti's research on complementary and alternative medicine influencing clinical dementia, neurodegeneration, and Alzheimer's disease has made him a pioneer in the field. He is the recipient of awards such as the Alzheimer's Association's Zenith Award and the Foundation Queen Sofia of Spain Research Center Award on Alzheimer's Disease. Pasinetti is a professor of neurology, psychiatry, neuroscience, and geriatrics and adult development and is chief of the Brain Institute Center of Excellence for Novel Approaches to Neurotherapeutics at Mount Sinai School of Medicine. He also serves as director of the Basic and Biomedical Research and Training, Geriatric Education and Clinical Center at the Bronx Veterans Affairs Medical Center. Pasinetti recently received an NIH-funded research grant supporting a Center of Excellence for Research in Complementary and Alternative Medicine in Alzheimer's disease. Pasinetti is the principal investigator and director of the center.
Pablo Ariel is a postdoctoral scientist in neuroscience at Columbia University, where he is developing tools to shut down specific brain circuits in behaving animals. Originally from Argentina, he now lives in New York City with his wife, who is also a scientist.