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Scripps research team reveals how an old drug could have a new use for treating river blindness
Date:2/9/2010

d drugs and 432 are foreign-approved drugsto screen for active compounds.

"We were looking for a molecule that had a dramatic effect on chitanase specific to O. volvulus," Gloeckner explains. "The chitinase's enzymatic activity was monitored by a fluorescent signal. A library member was scored as a "hit" when a decrease in the signal was observed. Simply stated when a huge decrease in the signal was observed, the enzyme was essentially "knocked-out."

The screening efforts identified four known drugs namely levfloxacin, lomefloxacin, dexketoprofen, and closantel. Of these, only closantel was found to exhibit potent enough inhibition to warrant further investigation.

Cross-Country Collaboration

The next step was to find out if closantel would work in vivo, in the larvae of O. volvulus.

"The molting process is considered a potential new target for chemotherapy against onchocerciasis," Gloeckner explains. "And since chitinases may play a key role in molting, we wanted to determine the effect of closantel on this process." Specifically, the researchers were interested in how clostanel would disrupt molting from the L3 to L4 stage of the larvae, a critical step that occurs within the human host.

That's when the Scripps Research team enlisted the help of Sara Lustigman's laboratory at the Lindsley F. Kimball Research Institute at the New York Blood Center. Lustigman's team cultured L3-stage larvae in the presence of increasing concentrations of closantel, and the number of larvae was determined on day six. The results? Closantel completely prevented molting from the L3 to L4 stage.

Gloeckner was excited by this finding. "Based on its specificity, potency, and ease of synthesis, closantel or one its analogues might represent a promising alternative or adjunct therapy in combination with ivermectin for the treatment of onchocerciasis," he says.

Gloeckner adds that, bas
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Contact: Keith McKeown
kmckeown@scripps.edu
858-784-8134
Scripps Research Institute
Source:Eurekalert

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