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Cruzipain Inhibitors Show Potential for Treatment of Chagas Disease

By BiotechDaily International staff writers
Posted on 08 Jan 2014
Image: Trypanosoma cruzi in blood smear from patient with trypanosomiasis (Photo courtesy of the CDC – [US] Centers for Disease Control and Prevention).
Image: Trypanosoma cruzi in blood smear from patient with trypanosomiasis (Photo courtesy of the CDC – [US] Centers for Disease Control and Prevention).
A new generation of antiparasitic drugs based on inhibitors of the enzyme cruzipain has been shown to have potential for more effective treatment of the chronic form of Chagas disease.

Chagas disease or American trypanosomiasis, caused by the parasite Trypanosoma cruzi, affects about 18 million people living mostly in Latin America.

The current drug of choice for treating Chagas is benznidazole. Its mechanism of action is the production of free radicals, to which the T. cruzi is particularly sensitive. Benznidazole has a significant activity during the acute phase of the disease, with a success rate of up to 80%. Its curative capabilities during the chronic phase are, however, limited. Some studies have found parasitologic cure (a complete elimination of T. cruzi from the body) in pediatric and young patients during the early stage of the chronic phase, but overall failure rate in chronically infected individuals is typically above 80%.

Investigators at the Merck Frosst Center for Therapeutic Research (Kirkland, QC, Canada) focused on a different approach to killing T. cruzi: inhibition of the enzyme cruzipain. This enzyme is a cysteine proteinase that hydrolyzes chromogenic peptides at the carboxyl arginine or lysine residue. It requires at least one more amino acid between the terminal arginine or lysine and the amino-blocking group. The purified enzyme digests itself. The enzyme plays a critical role in the development and differentiation of T. cruzi.

The investigators treated mice with acute T. cruzi infection with oral doses of two key cruzipain inhibitors, Cz007 and Cz008, in chow for 28 days. Parasite presence in blood, heart, and esophagus was evaluated.

Results published in the December 9, 2013, online edition of the journal Antimicrobial Agents and Chemotherapy revealed that based on negative qPCR in all three tissues, cure rates in surviving animals were 90% for Cz007, 78% for Cz008, and 71% for benznidazole, the control compound.

"The efficacy shown in these T. cruzi murine studies suggests that nitrile-containing cruzipain inhibitors show promise as a viable approach for a safe and effective treatment of Chagas disease," said senior author Dr. Deborah Nicoll-Griffith, a researcher at the Merck Frosst Center for Therapeutic Research. "While historically infection was largely confined to poor and rural populations in Central and South America, it has been emerging in the US, Canada, Europe, Japan, and Australia, due to immigration, and nonvectorial transmission is becoming a public health threat."

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Merck Frosst Center for Therapeutic Research




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