Novel Peptidyl Cysteine Inhibitor Cures Hookworm Infection in Hamster Model

A candidate drug about to enter clinical trials for the treatment of Chagas disease has been found to be a potent killer of the hookworm parasite with a single dose destroying more than 90% of the worms in infected hamsters.

Hookworm disease is a major global health problem and principal among a number of soil-transmitted helminthiases for the chronic disability inflicted that impacts both personal and societal productivity. Mass drug administration most often employs single-dose therapy with just two drugs of the same chemical class to which resistance is a growing concern. In spite of the enormous prevalence of hookworm disease (up to 1.2 billion cases worldwide), just two drugs, albendazole and mebendazole, are most commonly employed for treatment and control, and both belong to the same benzimidazole chemical class. There exists, therefore, a pressing need to develop new, safe and inexpensive agents for the treatment of human nematode infections of global significance.

The candidate drug under study, K11777 is a peptidyl cysteine protease inhibitor (CPI) that blocks the action of an enzyme required by the parasite for digestion of its blood meal. K11777 is chemically distinct from all the current antihelmintics and, therefore, not likely to share resistance characteristics.

Investigators at the University of California, San Francisco (USA) and their colleagues at Yale University (New Haven, CT, USA) worked with various life-cycle stages of the hookworm Ancylostoma ceylanicum in vitro and with a hamster model of hookworm infection.

They reported in the July 3, 2012, online edition of the journal PLoS Neglected Tropical Diseases that K11777 killed first-stage hookworm larvae with a potency equal to that of the current antihookworm drug, albendazole (ABZ). Furthermore, the drug produced morbidity in adult hookworms in vitro with the activity of K11777 again being at least the equivalent of ABZ. Combinations K11777 with ABZ enhanced morbidity compared to single compounds. Oral treatment of infected hamsters with two 100 mg/kg dose of K11777 for one day cured infection, while a single 100 mg/kg dose removed more than 90% of worms. Treatment also reversed the otherwise fatal decrease in blood hemoglobin levels and body weights of hosts.

“The harbinger of concern is that for worm parasites of cattle and sheep, there is rampant resistance to the same or similar drugs that are currently being used to treat humans,” said senior author Dr. Conor Caffrey, senior research associated in the pathology department of the University of California, San Francisco. “Up to now, these have performed reasonably well but we are starting to hear reports of lower effectiveness, so we are working hard to identify new drug candidates before the inevitable happens.”

“Even if K11777 does not end up as a new therapy, the discovery opens the door to developing cysteine protease inhibitors as a new class of drugs to treat hookworm and, perhaps, other intestinal nematode infections,” said Dr. Caffrey. “This also could have ramifications for treating similar parasites in the animal health industry.”

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University of California, San Francisco
Yale University