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JUPITER, FL, Feb. 14, 2017 - A pair of scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded up to $3.3 million from the National Cancer Institute of the National Institutes of Health (NIH) to create the next generation of breast cancer treatments for the thousands of patients whose current treatment options are limited. Ben Shen, TSRI professor and co-chair of the Department of Chemistry, and Christoph Rader, TSRI associate professor in the Department of Immunology and Microbiology, will co-lead the new five-year study. The researchers aim to develop a potent type of therapy known as an antibody-drug conjugate (ADC). This new class of anti-cancer drugs combines the specificity of antibodies, which attack only cells they recognize, with a highly toxic payload designed to kill specific cancer cells with far greater efficiency than most currently available treatments. So far, only three of these combination therapies have been approved by the U.S. Food and Drug Administration (FDA). The new ADC approach targets HER2-postive and ROR1-positive breast cancers, which are often aggressive and harder to treat with conventional chemotherapy and hormone drugs. The new grant builds on the work done in both the Shen and Rader labs. Shen and his colleagues recently uncovered a new class of natural products called tiancimycins, (TNMs) which kill selected cancer cells more rapidly and more completely compared with the toxic molecules already used in FDA-approved ADCs. Rader, who has spent most of his scientific career at TSRI and the NIH, has been studying and developing site-specific ADCs to treat cancer. "This grant matches my lab's work on advancing antibody engineering and conjugation technologies with the world-class natural product-based drug discovery in Ben Shen's lab," Rader said. "It's precisely what I came to Scripps Florida for: to build new molecules at the interface of chemistry and biology that can advance medicine. I'm very pleased that the NIH continues to invest in our ideas." Since HER2 and ROR1 expression is highly complementary, the new collaboration could provide new treatment options for at least 50 percent of breast cancer patients, Shen noted. "At Scripps Florida we not only do great science, but we have even greater opportunities to collaborate on projects like this," Shen added. "The combination of Christoph Rader's antibody technology and the tiancimycins, which have been proven to be exquisitely potent, should produce an antibody drug conjugate that we hope to move very quickly into the clinic." The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


LA JOLLA, CA - February 22, 2017 - The MagnaSafe Registry, a new multicenter study led by scientists at The Scripps Research Institute (TSRI), has demonstrated that appropriately screened and monitored patients with standard or non-MRI-conditional pacemakers and defibrillators can undergo MRI at a field strength of 1.5 tesla without harm. These devices are not presently approved by the U.S. Food and Drug Administration (FDA) for MRI scanning. The researchers observed no patient deaths, device or lead failures, losses of pacing function or ventricular arrhythmias in 1,500 patients who underwent MRI using a specific protocol for device interrogation, device programming, patient monitoring and follow-up designed to reduce the risk of patient harm from MRI effects. The research will be published as an Original Article in the February 23, 2017 issue of The New England Journal of Medicine. The use of MRI poses potential safety concerns for patients with an implanted cardiac device. These concerns are a result of the potential for magnetic field-induced cardiac lead heating, which could result in cardiac injury and damage to an implanted device. As a result, it has long been recommended that patients with a pacemaker or defibrillator not undergo MRI scanning, even when MRIs are considered the most appropriate diagnostic imaging method for their care. Despite the development of devices designed to reduce the potential risks associated with MRI, a large number of patients have devices that have not been shown to meet these criteria and are considered "non-MRI-conditional." At least half these patients are predicted to have the need for MRI after a device has been implanted. Researchers established the MagnaSafe Registry to determine the frequency of cardiac device-related events among patients with non-MRI-conditional devices, as well as to define a simplified protocol for screening, monitoring and device programming before MRI. "Given the great clinical demand for MRI for patients with a standard pacemaker or defibrillator, we wanted to determine the risk," said study leader Dr. Robert Russo, an adjunct professor at TSRI and director of The La Jolla Cardiovascular Research Institute. In the MagnaSafe Registry, researchers at 19 U.S. institutions tested 1,000 cases with a non-MRI-conditional pacemaker (one not approved for use in an MRI) and 500 cases of patients with a non-MRI-conditional implantable cardioverter defibrillator (ICD), a device that can shock the heart in response to a potentially fatal cardiac rhythm. They scanned regions other than the chest, such as the brain, spine or extremities--where MRI is traditionally the best option for imaging. The researchers tested the devices at an MRI field strength of 1.5 tesla, a standard strength for MRI scanners and reprogrammed some devices according to a prespecified protocol for the MRI examination. "If the patient was not dependent upon their pacemaker, the device was turned off," explained Russo. "If they could not tolerate having the device turned off, it was set to a pacing mode that did not sense cardiac activity. The reason was that the pacemaker could sense the electrical activity (radiofrequency energy) from the MRI scanner and the function of the device could be inhibited, which could be catastrophic if you depend upon your pacemaker for your heartbeat." Russo and his co-investigators did observe adverse effects in a small group of patients. Six patients had a brief period of atrial fibrillation, and in six additional cases pacemaker partial reset (a loss of stored patient information) was noted. But in no cases did the researchers observe device failure or a failure in the leads that connect the device to the heart when the protocol was followed. "One ICD generator could not be interrogated after MRI and required immediate replacement; the device had not been appropriately programmed per protocol before the MRI," explained Russo. These findings led the researchers to conclude that "device removal and replacement seem unlikely to be safer than proceeding with scanning for patients with a pacemaker or an ICD who require a nonthoracic MRI," provided a protocol similar to the MagnaSafe protocol was followed. "Patients with a standard or non-MRI-conditional pacemaker can undergo clinically indicated MRI without harm if a protocol such as the 'MagnaSafe' protocol used in this study is followed and patients are screened and monitored as described," said Russo. The researchers also noted that their results may not be predictive of findings with all device and lead combinations, higher MRI field strengths, patients younger than 18 years of age and MRI examinations of the chest or cardiac resynchronization devices (those designed to increase the function of a failing heart). The researchers plan to follow up by studying the risk for patients in need of a chest scan at scanner field strength of 1.5 tesla, as well as an MRI of any anatomic area at a higher field strength (3.0 tesla). The study, "Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator," also included authors from the University of California, San Diego; Scripps Memorial Hospital; the University of California, Los Angeles; Providence St. Joseph Medical Center; the University of Arizona; Intermountain Medical Center; Inova Heart and Vascular Institute; Allegheny General Hospital; Abington Memorial Hospital; Yale University School of Medicine; Providence Heart Institute; Oklahoma Heart Institute; the University of Mississippi Medical Center; the Medical College of Wisconsin; Bassett Medical Center; Carnegie Hill Radiology; Methodist DeBakey Heart and Vascular Center and Baptist Health. The study was supported by grants from St. Jude Medical, Biotronik, Boston Scientific and the Hewitt Foundation for Medical Research, and by philanthropic gifts from Mr. and Mrs. Richard H. Deihl, Evelyn F. and Louis S. Grubb, Roscoe E. Hazard, Jr. and the Shultz Steel Company. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


News Article | February 15, 2017
Site: www.eurekalert.org

JUPITER, FL - February 15, 2017 - Scientists are working to understand the mechanisms that make weight loss so complicated. Exercise burns calories, of course, but scientists are also looking at how the body burns more energy to stay warm in cold temperatures. Is there a way to get metabolism to ramp up--even when it's not cold out? TSRI Assistant Professor Anutosh Chakraborty is on a mission to answer this question. His past research revealed a new therapeutic target in this battle--a protein that actually promotes fat accumulation in animal models by slowing stored energy (fat) breakdown and encouraging weight gain. Now, in a study recently published online in the journal Molecular Metabolism, Chakraborty and his colleagues have shown that deleting the gene for this protein, known as IP6K1, protects animal models from both obesity and diabetes. This protective effect is seen regardless of diet, even at what's known as a thermoneutral temperature (around 86?F). This means inhibiting IP6K1 should help animals burn more energy, regardless of outside conditions. "In genetically altered animal models that lack IP6K1, we found that deletion dramatically protects these knock-out mice from diet-induced obesity and insulin resistance regardless of the temperature in the environment," Chakraborty said. "When we inhibited the enzyme with chemical compounds, the results were similar." Temperature is important in the study of obesity because an animal in lower temperatures will rapidly lose weight as it burns more energy to try to maintain core body temperature. Because humans can maintain their body temperatures in a number of ways--clothing, for example--any pathway that reduces body weight at higher temperatures is a highly encouraging target in human obesity. The new study suggests a future pharmaceutical may be able to target IP6K1 to mimic the energy burning seen at relatively lower temperatures. "If we delete IP6K1, the animals gain less body weight because they simply expend more energy--regardless of temperature. That's important because blocking weight gain by enhancing energy expenditure in a thermoneutral environment is harder and thus, targeting IP6K1 is expected to be successful in ameliorating obesity in humans," said Chakraborty. "If you're developing an anti-obesity drug based on inhibiting IP6K1, our new findings shows that there are potentially very few restrictions for its use--a subject would lose weight even on a high-fat diet, and nobody would have to sit in a refrigerator to make it work," he added. The first author of the study, "Global IP6K1 deletion enhances temperature modulated energy expenditure which reduces carbohydrate and fat induced weight gain," is TSRI's Qingzhang Zhu. Other authors are Sarbani Ghoshal, at TSRI at the time of the study, now at the Saint Louis University School of Medicine, and Richa Tyagi of the Johns Hopkins University School of Medicine. This work is supported by the National Institutes of Health (grant R01DK103746) and the state of Florida. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


LA JOLLA, Calif., Feb. 22, 2017 (GLOBE NEWSWIRE) -- ActivX Biosciences, Inc.®, a wholly owned subsidiary of Kyorin Pharmaceutical Co., Ltd. (Tokyo), announces the appointment of Professor Hugh Rosen of The Scripps Research Institute to the position of Chairman & President of ActivX®, effective April 1, 2017. He will succeed John W. Kozarich who has been at ActivX since 2001, serving as Chairman & President since its acquisition by Kyorin in 2004. John will stay on at ActivX as a Board Director and assume the new position of Distinguished Scientist and Executive Advisor. Professor Rosen’s 30+ year career in the pharmaceutical, biotechnology and academic sectors has been one of significant achievements. Following training in medicine in Cape Town, he received his D.Phil. as a Royal Commission for the Exhibition of 1851 Scholar at the University of Oxford.  He spent 11 years at Merck Research Laboratories before becoming a Professor at TSRI (The Scripps Research Institute) in 2002. There he co-invented ozanimod and was a scientific founder of Receptos, acquired by Celgene in 2015 for $7.3 Billion, as well as BlackThorn Therapeutics, which recently closed a $40M Series A. He serves as an independent Board member at Regulus Therapeutics and will remain on the faculty of TSRI. “Hugh Rosen is a world-class translational physician/scientist and biotechnology entrepreneur,” explained Dr. Kozarich. “We are delighted that he will assume the leadership of ActivX, building on our R&D contributions to Kyorin and adding new dimensions to our cutting-edge KiNativ technology. Hugh has been a friend and colleague to me and to Kyorin for 25 years. I am honored to have him as my successor and look forward to working with him in my new role. Hugh’s appointment clearly signals Kyorin’s ongoing commitment to ActivX as a key component to their future success. This is an ideal outcome for all involved.” Dr. Rosen added that: “The opportunity to lead ActivX Biosciences is especially attractive to a physician-scientist with a record of success in drug discovery and development because the ActivX technologies have unlocked exciting and potentially transforming drug discovery opportunities. This is a tribute to the outstanding work of John Kozarich and colleagues at both ActivX and Kyorin.  I look forward to continuing to work with John, his management team and Kyorin to bring significant new products forward to benefit patient outcomes, caregivers and providers. Through discovery and development, we strive to improve the public health.” Mr. Minoru Hogawa, Representative Director, President and Chief Executive Officer of Kyorin Holdings Inc., commented that: “Kyorin has been and will be creating first-in-class medicines. ActivX Biosciences is the core member for our research group activities. We believe Dr. Rosen will accelerate our research programs and accomplish our goals effectively with his wide experience.” ActivX Biosciences, Inc.® (www.activx.com ) located in La Jolla, California, is a wholly-owned subsidiary of Tokyo-based Kyorin Pharmaceutical Co., Ltd., and has drug discovery and proteomics technology capabilities. The company applies proprietary chemical technologies and high-throughput protein analysis to the drug discovery and development process. By focusing on functional proteins, ActivX® addresses disease mechanisms directly, in contrast to approaches such as expression profiling, in which the measured analyte is several steps removed from the site of drug action. ActivX and its partners utilize ActivX’s proprietary technology and profiling platform (KiNativ® - www.kinativ.com ) to address critical challenges in kinase drug discovery, including selectivity profiling of candidate drug molecules in biological samples to guide their medicinal chemistry efforts. The KiNativ platform aids in the identification of novel drug targets and biomarkers, the determination of target engagement in vivo and the characterization of off-target activities of candidate and established drugs to understand the basis of their efficacy and/or toxicity. About Kyorin Pharmaceutical Co., Ltd. Trusted among patients and professionals in the medical industry, Kyorin Pharmaceutical Co., Ltd. (http://www.kyorin-pharm.co.jp/en/), which is a core company of Kyorin Holdings Inc. (http://www.kyorin-gr.co.jp/en/), strives to be a company that contributes to the public health and is recognized as a one with social significance by improving its presence in specified therapeutic areas and through global discovery of novel drugs. Kyorin Pharmaceutical Co., Ltd. uses its franchise customer strategy in the developing and marketing ethical drugs on the core areas of respiratory, otolaryngology and urology.


News Article | September 27, 2016
Site: www.biosciencetechnology.com

A study by scientists at The Scripps Research Institute (TSRI) has helped to de-mystify the molecular workings of the multiple sclerosis (MS) drug Tecfidera. The drug is the most widely prescribed pill-based therapy for MS, but its biological mechanism remains mysterious. Using a new TSRI technology that can quickly reveal a drug’s protein targets, the scientists showed that Tecfidera interacts with multiple T cell proteins, in some cases inhibiting their activity, and helping to suppress the T cell activation that is a key feature of MS flare-ups. “This new technology has given us insights into the therapeutic modulation of the immune system that we could not have obtained with standard approaches,” said co-senior author John R. Teijaro, an assistant professor at TSRI. The study was reported recently in Science Signaling. MS is an autoimmune disease of the brain featuring damage to nerve fibers and producing a range of symptoms, including tingling in the extremities, muscle weakness, muscle spasms, visual problems and mood instability. About 400,000 people in the United States and about 2.5 million worldwide have MS, mostly in a form with intermittent flare-ups of symptoms—which can start to worsen inexorably. Two large clinical trials published in 2012 found that Tecfidera is almost twice as effective as an older standard MS drug at reducing the rate of flare-ups. It also appears to slow the disease’s progression. But how the drug works has never been clear. Despite its recent (2013) US Food and Drug Administration approval for MS, the drug is neither new nor high-tech. It is a relatively simple organic compound, dimethyl fumarate (DMF), that has been in the biomedical literature for decades. It was once used in Europe to prevent mold growth in sofas during storage and shipping, although the European Union banned it from consumer products in 2009 after it was linked to severe allergic skin reactions. It has proved more useful as a pharmaceutical: since the 1990s it has been an effective treatment—as the main ingredient in the drug Fumaderm—for the autoimmune skin disease psoriasis. Success against psoriasis led to its investigation as a potential MS drug. Until recently, the leading theory was that DMF works against MS primarily by unleashing the activity of a protein called Nrf2, which helps protect the brain from autoimmune damage by marshaling a powerful anti-oxidant response and which may also reduce immune system activation. Studies published in the past year have suggested, however, that DMF works principally by reducing immune system activity and does so independently of Nrf2. In recent years, there have also have been several reports among patients taking Fumaderm or Tecfidera of a potentially fatal viral brain infection called progressive multifocal leukoencephalopathy, which normally occurs only in people whose immune systems have been seriously weakened. To get a clearer picture of the pathways through which DMF works against MS, co-senior author Benjamin F. Cravatt, chair of the Department of Chemical Physiology at TSRI, and first author Megan M. Blewett, a PhD candidate at TSRI, teamed up with Teijaro to show that DMF inhibits the activation of human T cells. To identify the proteins targeted by DMF in these cells, the team then used a new research tool developed in the Cravatt laboratory. Described in a paper in Nature Methods in 2014, the tool enables researchers to globally map targets of a given drug compound in a complex sample of proteins, even the many thousands of proteins contained in live cells in a lab dish. The process specifically reveals where a compound makes very strong “covalent” bonds with cysteine amino acids on the proteins, cysteines being common targets of reactive drug molecules such as DMF. In this way, the team found that within activated human T cells, DMF reacts with about 50 different cysteines, in about as many proteins. The affected proteins include enzymes and regulators of gene activity. “Several are known as members of the NF-κB signaling pathway, a critical pathway for T cell activation,” said Blewett. The team confirmed that DMF blocks the activation of T cells, and that it does so, at least in part, by targeting two cysteine residues on the immune cell signaling enzyme PKCθ, thereby preventing PKCθ from associating with CD28, another protein needed for proper T cell activation. Even in T cells lacking PKCθ, DMF was able to reduce signs of activation further. That and other evidence strongly suggest that DMF’s full immune-damping impact results from its interactions with multiple proteins. “People often assume that a given drug works by hitting one target, but DMF likely produces its immunomodulatory effects by hitting multiple targets,” Blewett said. “This study shows the value of applying large-scale chemical profiling methods to primary human cells to gain insights into the mechanism of action of an important immunomodulatory drug,” Cravatt said. Cravatt, Teijaro, Blewett and their colleagues are now using the “target map” generated by this study to pursue the development of other compounds that might modulate immune activity in a more precise manner—hitting only the most important cysteine targets, for example on PKCθ—with fewer side-effects. “We’re interested ultimately in making more selective, site-specific drugs, both to reduce immune activity and to boost it,” said Teijaro. He credits the strong multidisciplinary environment of TSRI for the successful collaboration. “It really shows the strength of this place that chemical biologists can work with an immunologist like me to produce such valuable insights into drug therapy and the immune response,” Teijaro said.


February 21, 2017 - Results from a new Phase 3 study conducted by the Celgene Corporation demonstrate that ozanimod, a drug candidate originally discovered and optimized at The Scripps Research Institute (TSRI), can reduce the frequency of multiple sclerosis relapse. Relapsing multiple sclerosis is a form of the disease where patients experience a periodic worsening of symptoms. Sensory and motor loss of function leads to increased disability, and patients can need a cane or wheelchair. A signature of the disease is the appearance of lesions in the brain, which are linked to inflammation and can show up through MRI detection during active periods of multiple sclerosis relapse. Ozanimod, discovered by TSRI Professors Hugh Rosen and Ed Roberts and their laboratories, acts as a sphingosine 1-phosphate 1 (S1PR1) receptor agonist--modulating S1PR1 signaling and blocking sources of inflammation. Rosen and Roberts went on to co-found Receptos, a clinical stage biopharmaceutical company that took ozanimod into Phase 1, 2 and 3 clinical trials and was then acquired by Celgene. Ozanimod is the first New Chemical Entity discovered from a starting point in the NIH Common Fund Molecular Libraries Initiative to reach and succeed in advanced clinical studies. As reported by Celgene, results from the randomized, Phase 3, double-blind, double-dummy, active-controlled SUNBEAM study among 1,346 participants show that ozanimod met its primary endpoint in reducing annualized relapse rate (ARR) of relapsing multiple sclerosis, compared with an alternate drug treatment called weekly interferon (IFN) β-1a (Avonex®). Administered at doses of both 1 mg and 0.5 mg, ozanimod demonstrated statistically significant and clinically meaningful improvements, compared to Avonex®, for the primary endpoint of ARR and the measured secondary endpoints of the number of MRI-detected lesions and the number of new or enlarging "T2" MRI lesions at after a year of treatment. "It is exciting and rewarding to see the results of this new Phase 3 trial, which confirm the safety profile from the two-year extension data from the Phase 2 RADIANCE study and underscore ozanimod's efficacy in reducing the burden of MS symptoms on patients and their families," said Rosen. "We look forward to seeing the full study results, as well as the results from the Phase 3 study evaluating ozanimod in patients with ulcerative colitis." Scientists involved in the trial plan to present the full Phase 3 trial results at an upcoming international scientific meeting. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


News Article | April 27, 2016
Site: www.rdmag.com

For the first time, scientists at The Scripps Research Institute (TSRI) have solved the structure of the biological machinery used by a common virus to recognize and attack human host cells. The new structure gives scientists the first view of the glycoprotein of lymphocytic choriomeningitis virus (LCMV), a virus present on every continent except Antarctica. Not only does the research reveal important traits in LCMV, it also points to possible drug targets on LCMV’s close relative: Lassa virus. “LCMV has been a beacon that has illuminated immunology and virology for decades,” said TSRI Professor Erica Ollmann Saphire. “This structure provides the missing roadmap to understand how to defend against its extremely lethal cousin, Lassa virus.” The study was published April 25, 2016, in the journal Nature Structural & Molecular Biology. LCMV is a rodent-borne virus that rarely causes noticeable symptoms in people, although it can progress to cause dangerous swelling in the brain and spinal cord of immunocompromised patients and birth defects when contracted during pregnancy. Over the years, the virus has served as a tool for understanding how the body responds to viral infections. “LCMV was the experimental virus that has illuminated much of what we understand about immunology and virology,” said Saphire. These studies included work in Frank Dixon’s lab at the fledgling Scripps Clinic and Research Foundation. Saphire describes LCMV as a “beacon” for virology. TSRI Professor Michael Oldstone, co-author of the new study, did much of that foundational work on LCMV and has long recognized LCMV’s similarity to Lassa virus, which looks identical under an electron microscope and shares 65 percent identity in the glycoprotein gene. Lassa is a much more deadly disease, however, causing thousands of deaths every year. While LCMV is a critical research tool, in the past 80 years scientists have been missing an important piece of the puzzle: a structural understanding of the proteins LCMV uses to initiate infection. Solving that structure took 10 years and has led to interesting insights into members of the arenavirus family—and how to stop them. For the study, researchers in Saphire’s lab used a method called X-ray crystallography to build three-dimensional models of the viral machinery, called the surface glycoprotein, which LCMV uses to fuse with host cells. Building the models required the scientists to screen hundreds of crystals until they found one that was stable enough to yield the necessary data. When the team finally solved the structure, it showed that the surface glycoprotein is made up of a two-part “dimer.” The dimer is made of two identical complexes that point opposite directions—“It’s like a yin and yang,” said Saphire. Two protein subunits make up each complex. One subunit, termed GP1, attaches onto the cell to be infected. The other subunit, called GP2, serves as the infection machinery, launching the process by which the virus fuses into the cell and hijacks it for its own purposes. The researchers compared each complex to an ice cream cone: GP1 forms the scoop of ice cream and GP2 forms a cone that cradles the scoop. Then there’s a long drip (the N-terminal strand of GP1) running down the side of the cone. “This structure is extremely important scientifically because it’s the first pre-fusion structure for any arenavirus glycoprotein,” said TSRI Senior Research Associate Kathryn Hastie, who was co-first author of the study with Sébastien Igonet, formerly of TSRI, now at CALIXAR. The new view of the virus came with some big surprises. For one thing, the dimer suggested that LCMV’s structure is a sort of “missing link” between two classes of viruses. Class I viruses, such as HIV, have a three-part “trimer” structure forming their fusion machinery while class II viruses, such as dengue, have a more rounded protein coat covering the whole virus. LCMV’s dimer lies flat, like class II proteins, but it likely brings in a third subunit later, creating a class I-like trimer. “It has moving parts,” explained Saphire. She added that LCMV now looks like it sits between class I and class II viruses, making this structure a possible “fossil” of an intermediate evolutionary process. In work spearheaded by TSRI biologist Brian Sullivan, the researchers studied how LCMV assembles and interacts with cells. By adding individual mutations to the genes for LCMV’s surface glycoprotein, the researchers identified five protein “residues” necessary for the virus to bind to host cells. These experiments also showed that, although the dimer is just a stage in the LCMV life cycle, it is a particularly critical stage. Disruption of the dimeric structure prevents viral growth. What This Means for Lassa Virus The researchers said these findings shed light on how this viral machine moves and rotates during infection, an action that could be blocked by drugs and antibodies. The new study also raises questions as to the degree of similarity between Lassa and LCMV. Could the dimer structure be particular to LCMV or is it a shared feature? “That information, and the fold of the GP1-GP2 complex, will be critical in the design of antibody cocktails for the treatment of Lassa fever,” said Hastie.


News Article | December 21, 2016
Site: www.rdmag.com

Scientists from the Scripps Research Institute created an efficient screening process that can quickly find new “enediyne natural products,” which are essentially promising drug leads derived from soil microbes. The team, led by TSRI professor Ben Shen, Ph.D., used this technique to identify a new group of enediyne natural products named tiancimycins. These products can kill certain cancer cells more quickly and completely than the monoclonal antibodies used in conjunction with cytotoxic drugs that target only cancer cells, according to the official announcement. "The enediynes represent one of the most fascinating families of natural products for their extraordinary biological activities," said Shen in a statement. "By surveying 3,400 strains from the TSRI collection, we were able to identify 81 strains that harbor genes encoding enediynes. With what we know, we can predict novel structural insights that can be exploited to radically accelerate enediyne-based drug discovery and development." Essentially, Shen’s method involved prioritizing the microbial strains that could produce the most important natural compounds enabling a more efficient allocation of resources during the discovery process. Other researchers have used similar methods to sift through large amounts of data in order to pinpoint promising compounds to treat diseases. A team at the Broad Institute of MIT and Harvard performed a similar process where they searched through a large chemical compound database for experimental malaria drugs with previously unknown novel mechanisms of action. Shen and his colleagues published their work in the journal mBIO.


News Article | February 15, 2017
Site: www.chromatographytechniques.com

Scientists are working to understand the mechanisms that make weight loss so complicated. Exercise burns calories, of course, but scientists are also looking at how the body burns more energy to stay warm in cold temperatures. Is there a way to get metabolism to ramp up--even when it's not cold out? TSRI Assistant Professor Anutosh Chakraborty is on a mission to answer this question. His past research revealed a new therapeutic target in this battle--a protein that actually promotes fat accumulation in animal models by slowing stored energy (fat) breakdown and encouraging weight gain. Now, in a study recently published online in the journal Molecular Metabolism, Chakraborty and his colleagues have shown that deleting the gene for this protein, known as IP6K1, protects animal models from both obesity and diabetes. This protective effect is seen regardless of diet, even at what's known as a thermoneutral temperature (around 86?F). This means inhibiting IP6K1 should help animals burn more energy, regardless of outside conditions. "In genetically altered animal models that lack IP6K1, we found that deletion dramatically protects these knock-out mice from diet-induced obesity and insulin resistance regardless of the temperature in the environment," Chakraborty said. "When we inhibited the enzyme with chemical compounds, the results were similar." Temperature is important in the study of obesity because an animal in lower temperatures will rapidly lose weight as it burns more energy to try to maintain core body temperature. Because humans can maintain their body temperatures in a number of ways--clothing, for example--any pathway that reduces body weight at higher temperatures is a highly encouraging target in human obesity. The new study suggests a future pharmaceutical may be able to target IP6K1 to mimic the energy burning seen at relatively lower temperatures. "If we delete IP6K1, the animals gain less body weight because they simply expend more energy--regardless of temperature. That's important because blocking weight gain by enhancing energy expenditure in a thermoneutral environment is harder and thus, targeting IP6K1 is expected to be successful in ameliorating obesity in humans," said Chakraborty. "If you're developing an anti-obesity drug based on inhibiting IP6K1, our new findings shows that there are potentially very few restrictions for its use--a subject would lose weight even on a high-fat diet, and nobody would have to sit in a refrigerator to make it work," he added.


News Article | February 21, 2017
Site: www.prnewswire.com

LA JOLLA, Calif. and JUPITER, Fla., Feb. 21, 2017 /PRNewswire-USNewswire/ -- The Scripps Research Institute (TSRI), one of the world's largest, private, non-profit research organizations, today announced the appointment of nine new members to its Board of Directors, including John D....

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