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LA JOLLA, CA - May 24, 2017 - Botulinum neurotoxin is probably best known to Americans as BOTOX, a cosmetic medicine, rather than as a cause of potentially dangerous foodborne illnesses. Lesser known is that Clostridium botulinum, the bacterium that causes the neurointoxication, produces one of the most potent toxins on earth and is classified as a potential bioterrorism threat. While no cure exists--and botulism treatment options are limited--a serendipitous discovery by scientists at The Scripps Research Institute (TSRI) may provide a new therapy that can stop the neurotoxin even in its more severe, advanced stages of action. The finding, based on rodent studies, was published recently in the Journal of the American Chemical Society. Lead scientist Kim Janda, the Ely R. Callaway, Jr. Professor of Chemistry at TSRI, said he decided to explore botulism neurotoxin due to its debilitating and life-threatening effects, as well as its danger as a potential bioterrorism agent. "It's on the same level as Anthrax, Plague, Ebola and other Category A priority pathogens," Janda said, referring to the Centers for Disease Control and Prevention's (CDC) list of biological agents of highest concern. "Yet there is nothing even in phase I clinical trials." Botulism is a rare but serious disorder that attacks the body's ability to signal to muscles. Symptoms include blurry vision, slurred speech, muscle weakness and difficulty swallowing. It can lead to paralysis throughout the body, and even death by affecting the patient's ability to breathe. According to the CDC, botulism is primarily transmitted through food or wounds infected by the botulism bacteria, which lives in the environment. In extremely small doses, the botulism toxin is injected for medical purposes, such as to relieve spasticity, and as a cosmetic wrinkle treatment. To discover potential inhibitors of the toxin, Janda and his research team screened triazole compounds against the botulinum neurotoxin light chain, a proteolytic enzyme that disrupts neuronal signaling to muscles. The triazoles were synthesized using click chemistry--a method developed by TSRI Professor and Nobel laureate K. Barry Sharpless in the mid-1990s. Paul Bremer, a graduate student working in Janda's laboratory and the study's first author, said they hit upon a triazole compound provided by Sharpless's laboratory that appeared to forcefully inhibit the toxin light chain in an enzymatic assay. Further testing revealed a surprise. "We had found what we thought were active click compounds, but really they were only active because of the copper," Bremer said. Copper is used as a catalyst to accomplish click chemistry and trace amounts would not be anticipated to show activity in a bioassay, he explained. "Upon further experiments, it came as a complete surprise that copper was quite potently inhibiting the enzyme." The scientists had accidentally landed upon a potential new therapy for type A of the neurotoxin, the most common and deadly cause of human botulism, using copper chloride, an inexpensive, readily available metal salt as the active ingredient. Next, the researchers designed molecules called ligands to act as delivery vehicles for copper into neuronal cells, an essential step in translating the therapeutic action of copper to biological systems. The TSRI team then sent their ligand-copper complexes to their study collaborators at the University of Wisconsin-Madison, who administered it to mice. The compound extended the animals' lives, even when they were given lethal doses of the toxin. The researchers said further animal testing is needed to determine optimal dosage, dosing frequency and other factors. Janda said clinical trials to prove efficacy cannot be done in humans due to botulinum neurotoxicity dangers. However, the safety of the copper complex can be validated through several other clinical trials already underway for different uses, he added. If found to be safe, Bremer said the copper therapeutic could provide a more effective therapy than existing approaches to botulism. Currently, botulism sufferers receive an anti-toxin medicine that can inactivate the toxin circulating in their system, thereby preventing further poisoning. However, the anti-toxin cannot reverse preexisting paralysis because the toxin acts inside cells. Consequently, disease recovery can be slow, and paralysis may take weeks or months to wear off. "The anti-toxin is antibody-based, which means it only works outside the cells," said Janda. "This new therapy can readily enter cells where it can attack the etiological agent, a protease, which is responsible for paralysis seen from the neurotoxin." The researchers also noted that the study further demonstrates the need to explore metals for therapeutic uses. Metals are not commonly used in drug design because of concerns about toxicity and specific targeting as compared to organic compounds. However, several metal-based therapies already exist. For instance, gold is used in therapies for certain cancers and rheumatoid arthritis, while other metal-based treatments are currently in clinical trials. "These are kind of underappreciated medicinal agents," said Bremer. "Our work shows the need to explore their potential further." The study, "Metal Ions Effectively Ablate the Action of Botulinum Neurotoxin A," was supported by the National Institutes of Health (grant R01A1119564.) In addition to Janda and Bremer, authors of the study include Lisa M. Eubanks of TSRI; Sabine Pellett, William H. Tepp and Eric A. Johnson of the University of Wisconsin-Madison; and James P. Carolan and Karen N. Allen of Boston University. 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 | May 25, 2017
Site: www.sciencedaily.com

With mosquito season looming in the Northern Hemisphere, doctors and researchers are poised to take on a new round of Zika virus infections. Now a new study by a large group of international researchers led by scientists at The Scripps Research Institute (TSRI) explains how Zika virus entered the United States via Florida in 2016 -- and how it might re-enter the country this year. By sequencing the virus's genome at different points in the outbreak, the researchers created a family tree showing where cases originated and how quickly they spread. They discovered that transmission of Zika virus began in Florida at least four -- and potentially up to forty -- times last year. The researchers also traced most of the Zika lineages back to strains of the virus in the Caribbean. "Without these genomes, we wouldn't be able to reconstruct the history of how the virus moved around," said TSRI infectious disease researcher and senior author of the study, Kristian G. Andersen, who also serves as director of infectious disease genomics at the Scripps Translational Science Institute (STSI). "Rapid viral genome sequencing during ongoing outbreaks is a new development that has only been made possible over the last couple of years." The research was published May 24, 2017, in the journal Nature. This was one of three related studies, published simultaneously in Nature journals, exploring the transmission and evolution of Zika virus. A fourth study was also published in Nature Protocols providing details of the technologies used by the researchers. By sequencing Zika virus genomes from humans and mosquitoes -- and analyzing travel and mosquito abundance data -- the researchers found that several factors created what TSRI Research Associate Nathan D. Grubaugh called a "perfect storm" for the spread of Zika virus in Miami. "This study shows why Miami is special," said Grubaugh, the lead author of the study. First, Grubaugh explained, Miami is home to year-round populations of Aedes aegypti mosquitoes, the main species that transmits Zika virus. The area is also a significant travel hub, bringing in more international air and sea traffic than any other city in the continental United States in 2016. Finally, Miami is an especially popular destination for travelers who have visited Zika-afflicted areas. The researchers found that travel from the Caribbean Islands may have significantly contributed to cases of Zika reaching the city. Of the 5.7 million international travelers entering Miami by flights and cruise ships between January and June of 2016, more than half arrived from the Caribbean. The researchers believe Zika virus may have started transmission in Miami up to 40 times, but most travel-related cases did not lead to any secondary infections locally. The virus was more likely to reach a dead end than keep spreading. The researchers found that one reason for the dead-ends was a direct connection between mosquito control efforts and disease prevention. "We show that if you decrease the mosquito population in an area, the number of Zika infections goes down proportionally," said Andersen. "This means we can significantly limit the risk of Zika virus by focusing on mosquito control. This is not too surprising, but it's important to show that there is an almost perfect correlation between the number of mosquitoes and the number of human infections." Based on data from the outbreak, Andersen sees potential in stopping the virus through mosquito control efforts in both Florida and other infected countries, instead of, for example, through travel restrictions. "Given how many times the introductions happened, trying to restrict traffic or movement of people obviously isn't a solution. Focusing on disease prevention and mosquito control in endemic areas is likely to be a much more successful strategy," he said. When the virus did spread, the researchers found that splitting Miami into designated Zika zones -- often done by neighborhood or city block -- didn't accurately represent how the virus was moving. Within each Zika zone, the researchers discovered a mixing of multiple Zika lineages, suggesting the virus wasn't well-confined, likely moving around with infected people. Andersen and Grubaugh hope these lessons from the 2016 epidemic will help scientists and health officials respond even faster to prevent Zika's spread in 2017. Understanding Zika's timeline required a large international team of scientists and partnerships with several health agencies. In fact, the study was a collaboration of more than 60 researchers from nearly 20 institutions, including study co-leaders at the U.S. Army Medical Research Institute of Infectious Diseases, Florida Gulf Coast University, the University of Oxford, the Fred Hutchinson Cancer Research Center, the Florida Department of Health and the Broad Institute of MIT and Harvard. The scientists also designed a new method of genomic sequencing just to study the virus. Because Zika virus is hard to collect in the blood of those infected, it was a challenge for the researchers to isolate enough of its genetic material for sequencing. To solve this problem, the team, together with Joshua Quick and Nick Loman at the University of Birmingham in the UK, developed two different protocols to break apart the genetic material they could find and reassemble it in a useful way for analysis. With these new protocols, the researchers sequenced the virus from 28 of the reported 256 Zika cases in Florida, as well as seven mosquito pools, to model what happened in the larger patient group. As they worked, the scientists released their data immediately publicly to help other scientists. They hope to release more data -- and analysis -- in real time as cases mount in 2017. The new study was published with three companion papers, also in Nature journals, that explore Zika's spread in other parts of the Americas.


News Article | May 25, 2017
Site: www.sciencedaily.com

Botulinum neurotoxin is probably best known to Americans as BOTOX, a cosmetic medicine, rather than as a cause of potentially dangerous foodborne illnesses. Lesser known is that Clostridium botulinum, the bacterium that causes the neurointoxication, produces one of the most potent toxins on earth and is classified as a potential bioterrorism threat. While no cure exists -- and botulism treatment options are limited -- a serendipitous discovery by scientists at The Scripps Research Institute (TSRI) may provide a new therapy that can stop the neurotoxin even in its more severe, advanced stages of action. The finding, based on rodent studies, was published recently in the Journal of the American Chemical Society. Lead scientist Kim Janda, the Ely R. Callaway, Jr. Professor of Chemistry at TSRI, said he decided to explore botulism neurotoxin due to its debilitating and life-threatening effects, as well as its danger as a potential bioterrorism agent. "It's on the same level as Anthrax, Plague, Ebola and other Category A priority pathogens," Janda said, referring to the Centers for Disease Control and Prevention's (CDC) list of biological agents of highest concern. "Yet there is nothing even in phase I clinical trials." Botulism is a rare but serious disorder that attacks the body's ability to signal to muscles. Symptoms include blurry vision, slurred speech, muscle weakness and difficulty swallowing. It can lead to paralysis throughout the body, and even death by affecting the patient's ability to breathe. According to the CDC, botulism is primarily transmitted through food or wounds infected by the botulism bacteria, which lives in the environment. In extremely small doses, the botulism toxin is injected for medical purposes, such as to relieve spasticity, and as a cosmetic wrinkle treatment. To discover potential inhibitors of the toxin, Janda and his research team screened triazole compounds against the botulinum neurotoxin light chain, a proteolytic enzyme that disrupts neuronal signaling to muscles. The triazoles were synthesized using click chemistry -- a method developed by TSRI Professor and Nobel laureate K. Barry Sharpless in the mid-1990s. Paul Bremer, a graduate student working in Janda's laboratory and the study's first author, said they hit upon a triazole compound provided by Sharpless's laboratory that appeared to forcefully inhibit the toxin light chain in an enzymatic assay. Further testing revealed a surprise. "We had found what we thought were active click compounds, but really they were only active because of the copper," Bremer said. Copper is used as a catalyst to accomplish click chemistry and trace amounts would not be anticipated to show activity in a bioassay, he explained. "Upon further experiments, it came as a complete surprise that copper was quite potently inhibiting the enzyme." The scientists had accidentally landed upon a potential new therapy for type A of the neurotoxin, the most common and deadly cause of human botulism, using copper chloride, an inexpensive, readily available metal salt as the active ingredient. Next, the researchers designed molecules called ligands to act as delivery vehicles for copper into neuronal cells, an essential step in translating the therapeutic action of copper to biological systems. The TSRI team then sent their ligand-copper complexes to their study collaborators at the University of Wisconsin-Madison, who administered it to mice. The compound extended the animals' lives, even when they were given lethal doses of the toxin. The researchers said further animal testing is needed to determine optimal dosage, dosing frequency and other factors. Janda said clinical trials to prove efficacy cannot be done in humans due to botulinum neurotoxicity dangers. However, the safety of the copper complex can be validated through several other clinical trials already underway for different uses, he added. If found to be safe, Bremer said the copper therapeutic could provide a more effective therapy than existing approaches to botulism. Currently, botulism sufferers receive an anti-toxin medicine that can inactivate the toxin circulating in their system, thereby preventing further poisoning. However, the anti-toxin cannot reverse preexisting paralysis because the toxin acts inside cells. Consequently, disease recovery can be slow, and paralysis may take weeks or months to wear off. "The anti-toxin is antibody-based, which means it only works outside the cells," said Janda. "This new therapy can readily enter cells where it can attack the etiological agent, a protease, which is responsible for paralysis seen from the neurotoxin." The researchers also noted that the study further demonstrates the need to explore metals for therapeutic uses. Metals are not commonly used in drug design because of concerns about toxicity and specific targeting as compared to organic compounds. However, several metal-based therapies already exist. For instance, gold is used in therapies for certain cancers and rheumatoid arthritis, while other metal-based treatments are currently in clinical trials. "These are kind of underappreciated medicinal agents," said Bremer. "Our work shows the need to explore their potential further."


While no cure exists—and botulism treatment options are limited—a serendipitous discovery by scientists at The Scripps Research Institute (TSRI) may provide a new therapy that can stop the neurotoxin even in its more severe, advanced stages of action. The finding, based on rodent studies, was published recently in the Journal of the American Chemical Society. Lead scientist Kim Janda, the Ely R. Callaway, Jr. Professor of Chemistry at TSRI, said he decided to explore botulism neurotoxin due to its debilitating and life-threatening effects, as well as its danger as a potential bioterrorism agent. "It's on the same level as Anthrax, Plague, Ebola and other Category A priority pathogens," Janda said, referring to the Centers for Disease Control and Prevention's (CDC) list of biological agents of highest concern. "Yet there is nothing even in phase I clinical trials." Botulism is a rare but serious disorder that attacks the body's ability to signal to muscles. Symptoms include blurry vision, slurred speech, muscle weakness and difficulty swallowing. It can lead to paralysis throughout the body, and even death by affecting the patient's ability to breathe. According to the CDC, botulism is primarily transmitted through food or wounds infected by the botulism bacteria, which lives in the environment. In extremely small doses, the botulism toxin is injected for medical purposes, such as to relieve spasticity, and as a cosmetic wrinkle treatment. To discover potential inhibitors of the toxin, Janda and his research team screened triazole compounds against the botulinum neurotoxin light chain, a proteolytic enzyme that disrupts neuronal signaling to muscles. The triazoles were synthesized using click chemistry—a method developed by TSRI Professor and Nobel laureate K. Barry Sharpless in the mid-1990s. Paul Bremer, a graduate student working in Janda's laboratory and the study's first author, said they hit upon a triazole compound provided by Sharpless's laboratory that appeared to forcefully inhibit the toxin light chain in an enzymatic assay. Further testing revealed a surprise. "We had found what we thought were active click compounds, but really they were only active because of the copper," Bremer said. Copper is used as a catalyst to accomplish click chemistry and trace amounts would not be anticipated to show activity in a bioassay, he explained. "Upon further experiments, it came as a complete surprise that copper was quite potently inhibiting the enzyme." The scientists had accidentally landed upon a potential new therapy for type A of the neurotoxin, the most common and deadly cause of human botulism, using copper chloride, an inexpensive, readily available metal salt as the active ingredient. Next, the researchers designed molecules called ligands to act as delivery vehicles for copper into neuronal cells, an essential step in translating the therapeutic action of copper to biological systems. The TSRI team then sent their ligand-copper complexes to their study collaborators at the University of Wisconsin-Madison, who administered it to mice. The compound extended the animals' lives, even when they were given lethal doses of the toxin. The researchers said further animal testing is needed to determine optimal dosage, dosing frequency and other factors. Janda said clinical trials to prove efficacy cannot be done in humans due to botulinum neurotoxicity dangers. However, the safety of the copper complex can be validated through several other clinical trials already underway for different uses, he added. If found to be safe, Bremer said the copper therapeutic could provide a more effective therapy than existing approaches to botulism. Currently, botulism sufferers receive an anti-toxin medicine that can inactivate the toxin circulating in their system, thereby preventing further poisoning. However, the anti-toxin cannot reverse preexisting paralysis because the toxin acts inside cells. Consequently, disease recovery can be slow, and paralysis may take weeks or months to wear off. "The anti-toxin is antibody-based, which means it only works outside the cells," said Janda. "This new therapy can readily enter cells where it can attack the etiological agent, a protease, which is responsible for paralysis seen from the neurotoxin." The researchers also noted that the study further demonstrates the need to explore metals for therapeutic uses. Metals are not commonly used in drug design because of concerns about toxicity and specific targeting as compared to organic compounds. However, several metal-based therapies already exist. For instance, gold is used in therapies for certain cancers and rheumatoid arthritis, while other metal-based treatments are currently in clinical trials. "These are kind of underappreciated medicinal agents," said Bremer. "Our work shows the need to explore their potential further." More information: Paul T. Bremer et al, Metal Ions Effectively Ablate the Action of Botulinum Neurotoxin A, Journal of the American Chemical Society (2017). DOI: 10.1021/jacs.7b01084


News Article | May 25, 2017
Site: www.biosciencetechnology.com

otulinum neurotoxin is probably best known to Americans as BOTOX, a cosmetic medicine, rather than as a cause of potentially dangerous foodborne illnesses. Lesser known is that Clostridium botulinum, the bacterium that causes the neurointoxication, produces one of the most potent toxins on earth and is classified as a potential bioterrorism threat. While no cure exists--and botulism treatment options are limited--a serendipitous discovery by scientists at The Scripps Research Institute (TSRI) may provide a new therapy that can stop the neurotoxin even in its more severe, advanced stages of action. The finding, based on rodent studies, was published recently in the Journal of the American Chemical Society. Lead scientist Kim Janda, the Ely R. Callaway, Jr. Professor of Chemistry at TSRI, said he decided to explore botulism neurotoxin due to its debilitating and life-threatening effects, as well as its danger as a potential bioterrorism agent. "It's on the same level as Anthrax, Plague, Ebola and other Category A priority pathogens," Janda said, referring to the Centers for Disease Control and Prevention's (CDC) list of biological agents of highest concern. "Yet there is nothing even in phase I clinical trials." Botulism is a rare but serious disorder that attacks the body's ability to signal to muscles. Symptoms include blurry vision, slurred speech, muscle weakness and difficulty swallowing. It can lead to paralysis throughout the body, and even death by affecting the patient's ability to breathe. According to the CDC, botulism is primarily transmitted through food or wounds infected by the botulism bacteria, which lives in the environment. In extremely small doses, the botulism toxin is injected for medical purposes, such as to relieve spasticity, and as a cosmetic wrinkle treatment. To discover potential inhibitors of the toxin, Janda and his research team screened triazole compounds against the botulinum neurotoxin light chain, a proteolytic enzyme that disrupts neuronal signaling to muscles. The triazoles were synthesized using click chemistry--a method developed by TSRI Professor and Nobel laureate K. Barry Sharpless in the mid-1990s. Paul Bremer, a graduate student working in Janda's laboratory and the study's first author, said they hit upon a triazole compound provided by Sharpless's laboratory that appeared to forcefully inhibit the toxin light chain in an enzymatic assay. Further testing revealed a surprise. "We had found what we thought were active click compounds, but really they were only active because of the copper," Bremer said. Copper is used as a catalyst to accomplish click chemistry and trace amounts would not be anticipated to show activity in a bioassay, he explained. "Upon further experiments, it came as a complete surprise that copper was quite potently inhibiting the enzyme." The scientists had accidentally landed upon a potential new therapy for type A of the neurotoxin, the most common and deadly cause of human botulism, using copper chloride, an inexpensive, readily available metal salt as the active ingredient. Next, the researchers designed molecules called ligands to act as delivery vehicles for copper into neuronal cells, an essential step in translating the therapeutic action of copper to biological systems. The TSRI team then sent their ligand-copper complexes to their study collaborators at the University of Wisconsin-Madison, who administered it to mice. The compound extended the animals' lives, even when they were given lethal doses of the toxin. The researchers said further animal testing is needed to determine optimal dosage, dosing frequency and other factors. Janda said clinical trials to prove efficacy cannot be done in humans due to botulinum neurotoxicity dangers. However, the safety of the copper complex can be validated through several other clinical trials already underway for different uses, he added. If found to be safe, Bremer said the copper therapeutic could provide a more effective therapy than existing approaches to botulism. Currently, botulism sufferers receive an anti-toxin medicine that can inactivate the toxin circulating in their system, thereby preventing further poisoning. However, the anti-toxin cannot reverse preexisting paralysis because the toxin acts inside cells. Consequently, disease recovery can be slow, and paralysis may take weeks or months to wear off. "The anti-toxin is antibody-based, which means it only works outside the cells," said Janda. "This new therapy can readily enter cells where it can attack the etiological agent, a protease, which is responsible for paralysis seen from the neurotoxin." The researchers also noted that the study further demonstrates the need to explore metals for therapeutic uses. Metals are not commonly used in drug design because of concerns about toxicity and specific targeting as compared to organic compounds. However, several metal-based therapies already exist. For instance, gold is used in therapies for certain cancers and rheumatoid arthritis, while other metal-based treatments are currently in clinical trials. "These are kind of underappreciated medicinal agents," said Bremer. "Our work shows the need to explore their potential further."


News Article | May 29, 2017
Site: www.sciencedaily.com

Scientists at The Scripps Research Institute (TSRI) have made another important advance in HIV vaccine design. The development was possible thanks to previous studies at TSRI showing the structures of a protein on HIV's surface, called the envelope glycoprotein. The scientists used these structures to design a mimic of the viral protein from a different HIV subtype, subtype C, which is responsible for the majority of infections worldwide. The new immunogen is now part of a growing library of TSRI-designed immunogens that could one day be combined in a vaccine to combat many strains of HIV. "All of this research is going toward finding combinations of immunogens to aid in protecting people against HIV infection," said TSRI Professor Ian Wilson, Hanson Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI. The research, published recently in the journal Immunity, was led by Wilson and TSRI Professor of Immunology Richard Wyatt, who also serves as Director of Viral Immunology for the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at TSRI. The new study was published alongside a second study in Immunity, led by scientists at the Karolinska Institute in Stockholm, which showed that the vaccine candidate developed in the TSRI-led study can elicit neutralizing antibodies in non-human primates. "Together, the two studies reiterate how structure-based immunogen design can advance vaccine development," said Wyatt. HIV mutates rapidly, so there are countless strains of HIV circulating around the world. Of these strains, scientists tend to focus on the most common threats, called clades A, B and C. Like a flu vaccine, an effective HIV vaccine needs to protect against multiple strains, so researchers are designing a set of immunogens that can be given sequentially or as a cocktail to people so their immune systems can prepare for whatever strain they come up against. In 2013, TSRI scientists, led by Wilson and TSRI Associate Professor Andrew Ward, determined the structure of a clade A envelope glycoprotein, which recognizes host cells and contains the machinery that HIV uses to fuse with cells. Because this is the only antibody target on the surface of HIV, an effective HIV vaccine will have to trigger the body to produce antibodies to neutralize the virus by blocking these activities. Building on the previous original research, the scientists in the new study set out to solve the structure of the clade C glycoprotein and enable the immune system to fight clade C viruses. "Clade C is the most common subtype of HIV in sub-Saharan Africa and India," explained study co-first author Javier Guenaga, an IAVI collaborator working at TSRI. "Clade C HIV strains are responsible for the majority of infections worldwide." The scientists faced a big challenge: the clade C envelope glycoprotein is notoriously unstable, and the molecules are prone to falling apart. Guenaga needed the molecules to stay together as a trimer so his co-author Fernando Garces could get a clear image of the clade C glycoprotein's trimeric structure. To solve this problem, Guenaga re-engineered the glycoprotein and strengthened the interactions between the molecules. "We reinforced the structure to get the soluble molecule to assemble as it is on the viral surface," Guenaga said. The project took patience, but it paid off. "Despite all the engineering employed to produce a stable clade C protein, these crystals (of clade C protein) were grown in very challenging conditions at 4 degrees Celsius and it took the diffraction of multiple crystals to generate a complete dataset, as they showed high sensitivity to radiation damage," said Garces. "Altogether, this highlights the tremendous effort made by the team in order to make available the molecular architecture of this very important immunogen." With these efforts, the glycoprotein could then stay together in solution the same way it remains together on the virus itself. The researchers then captured a high-resolution image of the glycoprotein using a technique called x-ray crystallography. The researchers finally had a map of the clade C glycoprotein. In a companion study, the scientists worked with a team at the Karolinska Institute to test an immunogen based on Guenaga's findings. The immunogen was engineered to appear on the surface of a large molecule called a liposome -- creating a sort of viral mimic, like a mugshot of the virus. This vaccine candidate indeed prompted the immune system to produce antibodies that neutralized the corresponding clade C HIV strain when tested in non-human primates. "That was great to see," said Guenaga. "This study showed that the immunogens we made are not artificial molecules -- these are actually relevant for protecting against HIV in the real world."


News Article | May 26, 2017
Site: www.eurekalert.org

LA JOLLA, CA - May 26, 2017 - Scientists at The Scripps Research Institute (TSRI) have made another important advance in HIV vaccine design. The development was possible thanks to previous studies at TSRI showing the structures of a protein on HIV's surface, called the envelope glycoprotein. The scientists used these structures to design a mimic of the viral protein from a different HIV subtype, subtype C, which is responsible for the majority of infections worldwide. The new immunogen is now part of a growing library of TSRI-designed immunogens that could one day be combined in a vaccine to combat many strains of HIV. "All of this research is going toward finding combinations of immunogens to aid in protecting people against HIV infection," said TSRI Professor Ian Wilson, Hanson Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI. The research, published recently in the journal Immunity, was led by Wilson and TSRI Professor of Immunology Richard Wyatt, who also serves as Director of Viral Immunology for the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at TSRI. The new study was published alongside a second study in Immunity, led by scientists at the Karolinska Institute in Stockholm, which showed that the vaccine candidate developed in the TSRI-led study can elicit neutralizing antibodies in non-human primates. "Together, the two studies reiterate how structure-based immunogen design can advance vaccine development," said Wyatt. HIV mutates rapidly, so there are countless strains of HIV circulating around the world. Of these strains, scientists tend to focus on the most common threats, called clades A, B and C. Like a flu vaccine, an effective HIV vaccine needs to protect against multiple strains, so researchers are designing a set of immunogens that can be given sequentially or as a cocktail to people so their immune systems can prepare for whatever strain they come up against. In 2013, TSRI scientists, led by Wilson and TSRI Associate Professor Andrew Ward, determined the structure of a clade A envelope glycoprotein, which recognizes host cells and contains the machinery that HIV uses to fuse with cells. Because this is the only antibody target on the surface of HIV, an effective HIV vaccine will have to trigger the body to produce antibodies to neutralize the virus by blocking these activities. Building on the previous original research, the scientists in the new study set out to solve the structure of the clade C glycoprotein and enable the immune system to fight clade C viruses. "Clade C is the most common subtype of HIV in sub-Saharan Africa and India," explained study co-first author Javier Guenaga, an IAVI collaborator working at TSRI. "Clade C HIV strains are responsible for the majority of infections worldwide." The scientists faced a big challenge: the clade C envelope glycoprotein is notoriously unstable, and the molecules are prone to falling apart. Guenaga needed the molecules to stay together as a trimer so his co-author Fernando Garces could get a clear image of the clade C glycoprotein's trimeric structure. To solve this problem, Guenaga re-engineered the glycoprotein and strengthened the interactions between the molecules. "We reinforced the structure to get the soluble molecule to assemble as it is on the viral surface," Guenaga said. The project took patience, but it paid off. "Despite all the engineering employed to produce a stable clade C protein, these crystals (of clade C protein) were grown in very challenging conditions at 4 degrees Celsius and it took the diffraction of multiple crystals to generate a complete dataset, as they showed high sensitivity to radiation damage," said Garces. "Altogether, this highlights the tremendous effort made by the team in order to make available the molecular architecture of this very important immunogen." With these efforts, the glycoprotein could then stay together in solution the same way it remains together on the virus itself. The researchers then captured a high-resolution image of the glycoprotein using a technique called x-ray crystallography. The researchers finally had a map of the clade C glycoprotein. In a companion study, the scientists worked with a team at the Karolinska Institute to test an immunogen based on Guenaga's findings. The immunogen was engineered to appear on the surface of a large molecule called a liposome--creating a sort of viral mimic, like a mugshot of the virus. This vaccine candidate indeed prompted the immune system to produce antibodies that neutralized the corresponding clade C HIV strain when tested in non-human primates. "That was great to see," said Guenaga. "This study showed that the immunogens we made are not artificial molecules--these are actually relevant for protecting against HIV in the real world." In addition to Wyatt, Wilson and Guenaga, the study, "Glycine substitution at helix-to-coil transitions facilitates the structural determination of a stabilized subtype C HIV envelope glycoprotein," included co-first author Fernando Garces, Natalia de Val, Viktoriya Dubrovskaya and Brett Higgins of TSRI; Robyn L. Stanfield of TSRI and IAVI; Barbara Carrette of IAVI; and Andrew Ward of TSRI, IAVI and the Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID) at TSRI. This work was supported by the IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD; grants OPP1084519 and OPP1115782), CHAVI-ID (grant UM1 AI00663) and the National Institutes of Health (grants P01 HIVRAD AI104722, R56 AI084817 and U54 GM094586). 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 | 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. .


News Article | May 11, 2017
Site: www.eurekalert.org

LA JOLLA, CA - May 11, 2017 - In their quest to replicate themselves, viruses have gotten awfully good at tricking human cells into pumping out viral proteins. That's why scientists have been working to use viruses as forces for good: to deliver useful genes to human cells and help patients who lack important proteins or enzymes. A team of researchers led by Associate Professor Vijay Reddy at The Scripps Research Institute (TSRI) has now uncovered the structural details that make one virus a better tool for future therapies than its closely related "cousin." As Reddy and his colleagues reported this week in the journal Science Advances, the structure of a less prevalent species D adenovirus may work well as a gene-delivery vector because its structure doesn't let it get spirited away to the liver, minimizing liver toxicity. The Reddy Lab's study is the first to show the structural details on species D's surface that set it apart from another common subtype of adenovirus, called species C, which does travel to the liver. "Greater understanding of the structures of adenoviruses from different species will help generate better gene therapies and/or vaccine vectors," said Reddy. Using an imaging technique called cryo-electron microscopy, the researchers discovered that while these two species of adenoviruses share the same shell-like core, they have different surface structures, which Reddy called "decorations" or "loops." These loops are key to a virus's behavior. They determine which receptors on human cells the virus can bind to. For species C adenoviruses, specific loops help the virus attach to blood coagulation factors (adaptor proteins) and get targeted to the human liver. Species D adenoviruses display distinctly different loop decorations. For use in gene and vaccine therapies, the virus would deliver helpful genes instead. Plus, species D has one more important advantage over species C: Humans are constantly exposed to species C adenoviruses, so most people have developed antibodies to fight them off. These same antibodies would fight off the species C viruses even if they were designed for beneficial therapies. On the flip side, many of the species D adenoviruses are rare, and it's unlikely that a patient would have antibodies to fight them off. That makes species D viruses better for delivering therapies. In fact, Reddy said scientists are already testing ways to use it to generate malaria and Ebola virus vaccines. The researchers next plan to look at members of the other five species of adenoviruses to see if they would have useful traits as viral therapy vectors. In addition to Reddy, the first authors of the study, "Cryo-EM structure of human adenovirus D26 reveals the conservation of structural organization among human adenoviruses," were Xiaodi Yu and David Veesler, formerly at TSRI, now at Pfizer Worldwide R&D, and the University of Washington, Seattle, respectively. Additional authors were Melody Campbell, formerly at TSRI, now at the University of California, San Francisco; Mary E. Barry and Michael A. Barry of the Mayo Clinic; and Francisco Asturias of TSRI. Reddy also thanked Bridget Carragher and Clint Potter, directors of the National Resource for Automated Molecular Microscopy (NRAMM) facility for their support and collaboration. The study was supported by the National Institutes of Health (grants R01AI070771, R21AI103692 and GM103310). 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. .


A team of researchers led by Associate Professor Vijay Reddy at The Scripps Research Institute (TSRI) has now uncovered the structural details that make one virus a better tool for future therapies than its closely related "cousin." As Reddy and his colleagues reported this week in the journal Science Advances, the structure of a less prevalent species D adenovirus may work well as a gene-delivery vector because its structure doesn't let it get spirited away to the liver, minimizing liver toxicity. The Reddy Lab's study is the first to show the structural details on species D's surface that set it apart from another common subtype of adenovirus, called species C, which does travel to the liver. "Greater understanding of the structures of adenoviruses from different species will help generate better gene therapies and/or vaccine vectors," said Reddy. Using an imaging technique called cryo-electron microscopy, the researchers discovered that while these two species of adenoviruses share the same shell-like core, they have different surface structures, which Reddy called "decorations" or "loops." These loops are key to a virus's behavior. They determine which receptors on human cells the virus can bind to. For species C adenoviruses, specific loops help the virus attach to blood coagulation factors (adaptor proteins) and get targeted to the human liver. Species D adenoviruses display distinctly different loop decorations. For use in gene and vaccine therapies, the virus would deliver helpful genes instead. Plus, species D has one more important advantage over species C: Humans are constantly exposed to species C adenoviruses, so most people have developed antibodies to fight them off. These same antibodies would fight off the species C viruses even if they were designed for beneficial therapies. On the flip side, many of the species D adenoviruses are rare, and it's unlikely that a patient would have antibodies to fight them off. That makes species D viruses better for delivering therapies. In fact, Reddy said scientists are already testing ways to use it to generate malaria and Ebola virus vaccines. The researchers next plan to look at members of the other five species of adenoviruses to see if they would have useful traits as viral therapy vectors. Explore further: Adenoviruses may pose risk for monkey-to-human leap More information: Xiaodi Yu et al, Cryo-EM structure of human adenovirus D26 reveals the conservation of structural organization among human adenoviruses, Science Advances (2017). DOI: 10.1126/sciadv.1602670

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