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Scientists Get Funding to Design Anti-Botulism Drugs

$1.4 million will aid Brookhaven Lab-Stony Brook researchers in quest for new treatments

UPTON, NY — Scientists at the U.S. Department of Energy’s Brookhaven National Laboratory (BNL), in collaboration with researchers at Stony Brook University’s Institute of Chemical Biology and Drug Discovery (ICB&DD), were selected to receive up to $1.4 million in applied research funds from the Department of Defense Defense Threat Reduction Agency (DTRA) to develop drugs that block the paralytic and deadly effects of botulinum neurotoxins.

Subramanyam Swaminathan

Brookhaven Biologist Subramanyam Swaminathan

“There are currently no reliable treatments for botulinum toxin exposure,” said Brookhaven biologist Subramanyam Swaminathan, who leads the collaborative effort. “It is important to develop a drug that combats the neurotoxic effects to mitigate fears associated with this deadly poison, including the fear of its potential use in bioterrorism attacks.”

Botulinum toxins are poisonous proteins produced by Clostridium botulinum bacteria. The toxins destroy essential components of nerve cells that control muscle movement, which prevents muscle functioning and leads to paralysis and death. Most commonly known for causing botulism poisoning from canned foods and for their use in cosmetic surgeries, botulinum toxins are the most potent neurotoxins known to humans and are considered extremely dangerous due to their potential use as a large-scale bioterrorism agent.

Fueling the need for developing new drugs is the fact that the current treatment for exposure to botulinum toxin is only effective if administered prior to the toxin infiltrating target cells — a critical time period that may pass before a diagnosis is even made.

The DTRA-funded project focuses on four main drug development goals, including:

  • deciphering the structure of enzyme-inhibitor complexes
  • screening large databases for candidate molecules and peptides that block the active sites of multiple botulinum toxin strains
  • synthesis of novel compounds and modification of molecules for broad spectrum use
  • and applying medicinal chemistry to optimize these compounds’ design.

Because there are seven different strains, or serotypes, of botulinum toxin — four of which affect humans — one important aspect of the project is developing a single drug that blocks the toxic effects of multiple strains.

“When inflicted by the neurotoxin, you don’t know which serotype you were infected with,” Swaminathan said. “Finding one common drug is useful because otherwise the specific serotype would need to be identified before treatment.”

Swaminathan has studied the botulinum neurotoxin proteins for over two decades and previously deciphered the structure of several strains of botulism toxin using x-ray crystallography data he collected at Brookhaven’s National Synchrontron Light Source (NSLS). The multi-disciplinary research project combines his enzyme-inhibitor structure work with the expertise and resources of Iwao Ojima and Peter Tonge of Stony Brook University’s Department of Chemistry and Robert Rizzo from the Department of Applied Mathematics and Statistics.

The drug development effort is the first consortium award between Brookhaven Lab and ICB&DD.

The NSLS is supported by the DOE Office of Science. The beamlines at NSLS used for this research are supported by the DOE Office of Science and the National Center for Research Resources at the National Institutes of Health.

2010-11078  |  INT/EXT  |  Media & Communications Office