California Institute for Biomedical Research

San Diego, CA, United States

California Institute for Biomedical Research

San Diego, CA, United States
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News Article | May 4, 2017
Site: www.eurekalert.org

JUPITER, FL - May 4, 2017 - Despite intense research, there's been much confusion regarding the exact role of a protein in a critical cancer-linked pathway. On one hand, the protein is described as a cell proliferation inhibitor, on the other, a cell proliferation activator, a duality that has caused a great deal of scientific head scratching. Now scientists from the Florida campus of The Scripps Research Institute (TSRI) have solved the conundrum, uncovering the regulatory machinery underlying the function of a protein, called angiomotin. The researchers found that angiomotin's activities depend on a process called phosphorylation--when a phosphate group is added to its structure at a specific location. Add a phosphate group, and the protein can inhibit cell proliferation. But remove a phosphate group from its normal makeup, and the protein promotes cell proliferation, encouraging cancer cell growth. The study, led by Joseph Kissil, associate professor in the Department of Molecular Medicine at TSRI, was recently published in the journal eLife. The new study sheds light on signaling pathway in cells called the Hippo-YAP pathway. YAP's involvement in cancer has been demonstrated in several tissues, including liver, intestine, heart, pancreas and brain. Recent studies show YAP plays a key role in developing drug resistance in lung and colon cancer cells and promoting cancer in some colon and pancreatic cancers. Hippo regulates cell proliferation and programmed cell death, which often become corrupted in diseases like cancer. Whether the Hippo-YAP pathway can be altered by the protein angiomotin is not in question. But while some studies give angiomotin a YAP-inhibitory function, others indicate that the protein is required for YAP activity. Kissil and his colleagues discovered what lies at the heart of those seemingly contradictory reports. They found that YAP forms a complex with angiomotin and another protein called Merlin. When angiomotin is phosphorylated, that changes the localization of this complex to the cell plasma membrane where it prevents cells from proliferating. "The relocation of the protein complex out of the nucleus to the plasma membrane prevents YAP from operating as a growth-promoting transcriptional activator," explained TSRI Graduate Student Sany Hoxha, co-first author of the study. Conversely, when angiomotin is less than fully phosphorylated, the complex is localized in the nucleus, where it promotes YAP-dependent cell proliferation. "Since this is a major pathway for diseases like cancer and fibrosis, our findings add a brand-new layer of valuable information," said Kissil. In addition to Kissil and Hoxha, the other first author of the study, "Regulation of Localization and Function of the Transcriptional Co-Activator YAP by Angiomotin," is Susana Moleirinho. Other authors include Vinay Mandati, Graziella Curtale and Scott Troutman of TSRI; and Ursula Ehmer of Technische Universität München, Munich, Germany. The study was supported by the National Institutes of Health (grants NS077952 and CA124495) and the Children's Tumor Foundation. 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 20, 2017
Site: www.rdmag.com

A team of chemists from the Scripps Research Institute (TSRI) developed a simple technique for creating a class of molecules that could yield valuable disease treatments. The researchers were able to transform abundant, inexpensive, structurally diverse carboxylic acids into boronic acids and related compounds with similar structures through a method called decarboxylative borylation. Essentially, this process entails harnessing a single reaction and cheap nickel catalysts to replace a key carbon atom with a boron atom on a carboxylic acid, according to the announcement. “Carboxylic acids are the ideal starting material for synthesizing boronic acids, but until now there hasn’t been any method for getting from one to the other,” said the principal investigator and professor of chemistry at TSRI Phil S. Baran, Ph.D., in a statement. Two experiments were performed to verify decarboxylative borylation’s efficacy. First, Baran and his team harnessed this technique to produce boronic acid versions of several commonly used drugs like vancomycin and atorvastatin (Lipitor). Next, the TSRI group worked with researchers from the California Institute for Biomedical Research (CIBR) to develop boronic-acid based compounds engineered to inhibit an enzyme known as neutrophil elastate. Immune cells release this enzyme in the lungs during infections involving lung inflammation, like chronic obstructive pulmonary disease and cystic fibrosis. Results from lab-dish tests indicated the boronic acid-based compounds had stronger elastase inhibitor capabilities compared to the other compounds, by binding very tightly to target molecules in a manner that allowed eventual detachment. This factor potentially limited the impact of off-target interactions that cause unwanted side-effects. “The next step is to see how well these compounds perform in animal models,” said study co-author and CIBR’s director of medicinal chemistry Arnab Chatterjee, in a statement. “In general, this new method allows us in a practical way to get into this largely unexplored but promising chemical space of borylated compounds, and thus enables us to revisit old targets, such as elastase, that have largely resisted prior drug development efforts.” Borylated versions of drug compounds should display superior properties compared to their carboxylic acid counterparts, but previous efforts to prepare these compounds were difficult, greatly limiting their use in the pharmaceutical industry. However, Baran notes that chemists can now efficiently install boron at any stage compared to devoting 95 percent of their time trying to introduce a single boron atom. These findings were published in the journal Science.


News Article | April 20, 2017
Site: www.rdmag.com

A team of chemists from the Scripps Research Institute (TSRI) developed a simple technique for creating a class of molecules that could yield valuable disease treatments. The researchers were able to transform abundant, inexpensive, structurally diverse carboxylic acids into boronic acids and related compounds with similar structures through a method called decarboxylative borylation. Essentially, this process entails harnessing a single reaction and cheap nickel catalysts to replace a key carbon atom with a boron atom on a carboxylic acid, according to the announcement. “Carboxylic acids are the ideal starting material for synthesizing boronic acids, but until now there hasn’t been any method for getting from one to the other,” said the principal investigator and professor of chemistry at TSRI Phil S. Baran, Ph.D., in a statement. Two experiments were performed to verify decarboxylative borylation’s efficacy. First, Baran and his team harnessed this technique to produce boronic acid versions of several commonly used drugs like vancomycin and atorvastatin (Lipitor). Next, the TSRI group worked with researchers from the California Institute for Biomedical Research (CIBR) to develop boronic-acid based compounds engineered to inhibit an enzyme known as neutrophil elastate. Immune cells release this enzyme in the lungs during infections involving lung inflammation, like chronic obstructive pulmonary disease and cystic fibrosis. Results from lab-dish tests indicated the boronic acid-based compounds had stronger elastase inhibitor capabilities compared to the other compounds, by binding very tightly to target molecules in a manner that allowed eventual detachment. This factor potentially limited the impact of off-target interactions that cause unwanted side-effects. “The next step is to see how well these compounds perform in animal models,” said study co-author and CIBR’s director of medicinal chemistry Arnab Chatterjee, in a statement. “In general, this new method allows us in a practical way to get into this largely unexplored but promising chemical space of borylated compounds, and thus enables us to revisit old targets, such as elastase, that have largely resisted prior drug development efforts.” Borylated versions of drug compounds should display superior properties compared to their carboxylic acid counterparts, but previous efforts to prepare these compounds were difficult, greatly limiting their use in the pharmaceutical industry. However, Baran notes that chemists can now efficiently install boron at any stage compared to devoting 95 percent of their time trying to introduce a single boron atom. These findings were published in the journal Science.


Patent
New York University and California Institute For Biomedical Research | Date: 2017-03-07

Provided are oxyntomodulin analogs. The peptide analogs have at least two cysteines. The two cysteines are separated by six amino acids such that they can be crosslinked using suitable crosslinking moieties. The crosslinked peptides have long half-lives and/or efficacy. For example, peptide analog compositions are used for inducing weight loss and/or reducing blood glucose levels.


News Article | May 9, 2017
Site: www.eurekalert.org

LA JOLLA, CA - May 9, 2017 - Three chemists from The Scripps Research Institute (TSRI)--Dale Boger, Jin-Quan Yu and Phil Baran--have received awards from the Royal Society of Chemistry (RSC), a renowned professional organization for chemists based in the United Kingdom, with more than 54,000 members worldwide. Dale Boger, co-chair of the Department of Chemistry at TSRI, was awarded the 2017 Robert Robinson Award of the RSC's Organic Division. The award honors his groundbreaking studies in natural product synthesis, which could lead to new therapeutic treatments for challenging clinical needs. "I am very honored and humbled to receive the RSC Robert Robinson Award, which has such a distinguished list of prior award winners," Boger said. Jin-Quan Yu, Frank and Bertha Hupp Professor of Chemistry at TSRI, received the 2017 Pedler Award from the RSC's Organic Division in recognition of his development of pioneering methods of C-H activation, a technique in chemistry that can lead to new pharmaceuticals and other natural products. "I hope these new reactions will accelerate the discovery and synthesis of useful molecules, especially medicines," said Yu, who received his Ph.D. in the U.K. at the University of Cambridge and served as a Royal Society fellow. "It gives me a warm feeling to be recognized by the U.K. scientific community that I was part of for 10 years." Phil Baran, the Darlene Shiley Professor of Chemistry at TSRI, received the RSC's 2017 Merck, Sharp & Dohme Award, which honors contributions to any area of organic chemistry from a researcher under the age of 45. Baran's work focuses on developing new chemical reactions and methodologies for more efficient and economically viable routes in drug design. Baran credited his lab members for his success so far. "This award is a recognition of the students and postdoctoral scholars who work tirelessly to invent useful chemistry," Baran said. In addition to £2,000 and a medal, all three awards include a lecture tour in the U.K. 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. .


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. .


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. .


News Article | January 27, 2016
Site: phys.org

To address that problem, scientists at the University at Buffalo and California Institute for Biomedical Research (Calibr) in La Jolla, California, are working to develop a therapy that could enable patients to control glucose levels while also losing weight. The treatment the researchers are developing is based on oxyntomodulin, a hormone that performs two important biological functions: First, it helps to keep glucose levels low by helping to increase insulin production. Second, the hormone encourages weight loss in part by facilitating processes that reduce food intake and increase the body's expenditure of energy. "On its own, oxyntomodulin has a short half-life. It's broken down quickly in the body, which means that patients would need to take it often and use high doses for it to work as a pharmaceutical," says Qing Lin, a chemistry professor in UB's College of Arts and Sciences. "We've modified the hormone's structure in a way that enhances its potency and enables it to survive in the body for longer periods of time, which allows for less frequent and more effective dosing." On Jan. 4 in ACS Chemical Biology, the researchers report that they have created several new versions of oxyntomodulin, including two that decreased blood glucose levels considerably in mice. Mice that received one of the two new compounds after ingesting glucose saw their glucose levels fall by 40 to 45 percent more than mice that received a placebo treatment. The two compounds also survived longer inside the animals than oxyntomodulin as it's found in nature. Lin was a senior author on the paper, along with Weijun Shen at Calibr. Lin has founded a startup, Transira Therapeutics, to further explore the potential therapy. In the body, oxyntomodulin regulates glucose levels and facilitates weight loss by binding to and activating two cellular receptors: the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). Oxyntomodulin performs its job best when it's in a certain helix conformation, but like many other peptide hormones, oxyntomodulin usually shifts between different shapes, including various helices and a random coil. Lin and his colleagues use a clever chemistry trick to help oxyntomodulin keep its helical shape. Their patented method is called chemical cross-linking. It involves engineering an oxyntomodulin molecule to include two groups of chemicals containing an amino acid called cysteine on different parts of the molecule, and then using a chemical linker to fasten those two groups together to make the molecule rigid. In cultured cells, cross-linked oxyntomodulin molecules were extremely effective in activating GCGR and GLP-1R, Lin and his colleagues reported in ACS Chemical Biology. The helical molecules are also harder for enzymes to break down, which helps the molecules survive longer in the body. Explore further: Surprise finding suggests diabetes drug could release rather than prevent blood sugar More information: Avinash Muppidi et al. Design of Potent and Proteolytically Stable Oxyntomodulin Analogs, ACS Chemical Biology (2016). DOI: 10.1021/acschembio.5b00787


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. .

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