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Scripps Florida scientists awarded $1.5M to fight major water and food parasites
Date:10/28/2008

This award includes $1.5 million granted to the laboratory of William Roush, Ph.D., of Scripps Florida, a division of The Scripps Research Institute. Other participants in the consortium are University of California, San Diego (UCSD), University of California, San Francisco (UCSF), and University of Washington.

Roush, executive director of the Scripps Florida Translational Research Institute Medical Chemistry division and professor in the Scripps Research Department of Chemistry, is a co-principal investigator for the project.

"Amebiasis and giardia are serious diseases that affect thousands of people in the United States and throughout the world," Roush said. "Our work, along with others in the consortium, is to develop new small molecule inhibitors that will target specific proteases that play a critical role in the lifecycle of these parasites and bring these agents to the pre-clinical development stage."

It has been estimated that up to 10 percent of the world's population is infected with Entamoeba histolytica, the one-celled parasite that causes amoebiasis. The parasite Giardia lamblia is the most common cause of water-borne protozoal infection in the United States, with more than 20,000 cases each year.

Various laboratory studies have noted that both parasites have developed resistance to antibiotic treatment, setting off alarm bells within the health care community.

"Because of the rise in parasitic resistance, the development of more effective treatments has become even more critical, especially if we want to prevent future outbreaks," Roush said. "This funding helps bring together the expertise of four major laboratories that will focus on finding a solution to this serious threat to human health.

Attractive Targets

Roush's laboratory is looking at cysteine proteases, which are common in protozoan parasites and are involved in nutrition and immune system evasion. What makes these proteases attractive as therapeutic targets is that they are found in a number of different parasites, and that synthetic inhibitor libraries have already been developed against this enzyme family.

As a result, a wealth of inhibitor leads already exist, many of which have been subject to extensive pharmacokinetic and safety studies; for example cysteine protease inhibitors have already demonstrated potent anti-trypanosomal effects.

"This family of enzymes is well known biochemically and structurally," Roush said, "and we understand the relationship between structure and function that involves active site specificity. Our laboratory has used this information to help design new inhibitors that attack targets critical to invasive Entamoeba histolytica."

The new inhibitor designed by Roush's laboratory attacks the EhCP1 (Entamoeba histolytica cysteine proteinase), which is believed to be a virulence factor of this parasite.

"We have designed a compound that has very good properties as an inhibitor of this particular protease," Roush said. "When you kill this enzyme, you kill the parasite's ability to infect human tissue. In animal models, this molecule behaves beautifully in that capacity. Unfortunately, it's not an orally bioavailable compound, so right now we're working to optimize it to make it orally available."


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Contact: Keith McKeown
kmckeown@scripps.edu
858-784-8134
Scripps Research Institute
Source:Eurekalert

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