Newly discovered small molecules
Findings could increase popular compound's therapeutic use and effectivenessAccording to the study, these activators bind to specific sites on the neurotoxin protein, increasing protease activity and enhancing the toxin's effect. In some cases, the study noted, the activation power of the new molecules was as much as fourteen-fold, the greatest increase in activation ever reported for a protease; before this study, a two-fold activation of a protease was referred to as a state of "superactivation." Proteases are enzymes that act as cellular catalysts, breaking up proteins into smaller elements such as amino acids and reducing the amount of energy needed for the activation.
The study was released in an advanced online version by the Journal of the American Chemical Society.
Kim Janda, currently the Ely R. Callaway Jr. professor of chemistry, director of the Worm Institute for Research and Medicine (WIRM), and head of the laboratory that conducted the study, said, "Since the botulinum neurotoxin is the most poisonous toxin known, finding a compound to activate it might seem somewhat counterproductive. But the range of clinical uses for the toxin have increased well beyond its cosmetic use--multiple sclerosis, stroke, cerebral palsy, migraine, and backache are just a few of the conditions for which BoNT has proven surprisingly effective. The discovery of small molecule activators may ultimately provide a valuable method for minimizing dosage, reducing resistance, and increasing its clinical efficacy."
Botulinum neurotoxins are the most lethal poisons known. They produce progressive paralysis by binding to nerves at the point where they connect to muscles, and blocking the release of acetylcholine, which signals the muscles to contract, including those that regulate breathing. Blocking the nerve signal results in paralysis and, unless treated quickly, death. A lethal dose is small--eight tenths of an inhaled microgram for a 175-pound person.
Because of its highly potent neurotoxic activity, Janda added, the use of BoNT is also of substantial global concern as a potential bioterrorist weapon.
One of the main drawbacks associated with BoNT as a therapeutic is that repeated use can lead to the development of a significant immune response. Tolerance to it develops most rapidly when patients receive frequent high doses of the toxin.
"We hypothesized that the use of BoNT in combination with a small molecule that could superactivate the action of the toxin would allow for lower doses," Janda said, "and reduce the patient's immune response. As the importance of BoNT in medicine continues to expand, we need to find some way to counter these unintended immune responses. Compounds like the ones we discovered, which produced the greatest protease activation ever recorded, may point the way to a potential solution."
Other authors of the study include Laura A. McAllister, Mark S. Hixon, Jack P. Kennedy, and Tobin J. Dickerson, all of the Scripps Research Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, and Worm Institute for Research and Medicine (WIRM).
The study, which can be accessed online at online at http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja057699z.html, was supported by the National Institutes of Health and The Skaggs Institute for Chemical Biology.
About The Scripps Research Institute
The Scripps Research Institute, headquartered in La Jolla, California, in 18 buildings on 40 acres overlooking the Pacific Ocean, is one of the world's largest independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel.
Scripps Florida, a 364,000 square-foot, state-of-the-art biomedical research facility, will be built in Palm Beach County. The facility will focus on basic biomedical science, drug discovery, and technology development. Palm Beach County and the State of Florida have provided start-up economic packages for development, building, staffing, and equipping the campus. Scripps Florida now operates with approximately 160 scientists, technicians, and administrative staff at 40,000 square-foot lab facilities on the Florida Atlantic University campus in Jupiter.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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