Indeed, the notion of вЂdrainingвЂ™ is apt as most pathology arises from adult worms that attach to and feed on intestinal mucosa and blood. Hookworm infection has been described as вЂsilent and insidiousвЂ™ and to вЂdrain out the vitalityвЂ™ of those afflicted due to chronic wasting and lethargy that has been often misconstrued as laziness. Hookworm zoonoses of minor medical importance also occur but these usually manifest with the restricted dermatitis condition of вЂcutaneous larva migransвЂ™, (e.g., and references therein). The principal etiological agents in humans are the nematodes Necator americanus (causing necatoriasis) and Ancylostoma duodenale (ancylostomiasis), although Ancylostoma ceylanicum is found in certain locales. One of a number of soil-transmitted helminthiases (STHs) that is deeply rooted in poverty, hookworm disease afflicts as much as 10% of the world's population in sub-Saharan Africa, South America, and South and South-East Asia. These results suggest that K11777 is on target to meet the current clinical practice and the logistics demanded for mass drug delivery of anthelmintics to humans (i.e., oral, single-dose treatment). Lastly, we report that K11777 provides near cure (>90%) of hookworm infection in a single oral administration (complete cure when given twice in one day). We describe mechanism of action studies that demonstrate that cysteine protease activity in parasites recovered after in vivo treatment with K11777 is almost completely (>95%) abrogated. K11777 is chemically distinct from all the current anthelmintics and, therefore, not likely to share resistance characteristics. We report the discovery of the striking efficacy of the cysteine protease inhibitor, K11777, against hookworms both in vitro and in vivo and discuss the development of this class of compounds as novel anthelmintics for the clinical management of hookworm disease. There exists, therefore, a pressing need to develop new, safe and inexpensive agents for the treatment of human nematode infections of global significance. In spite of the enormous prevalence of hookworm disease, just two drugs, albendazole and mebendazole, are most commonly employed for treatment and control, and both belong to the same benzimidazole chemical class. Consistent with its mechanism of action, K11777 decreased by >95% the resident CP activity in parasites harvested from hamsters 8 h post-treatment with a single 100 mg/kg oral dose. Treatment also reversed the otherwise fatal decrease in blood hemoglobin levels and body weights of hosts. (i.e., a total daily dose of 200 mg/kg) for one day cured infection: a single 100 mg/kg treatment removed >90% of worms. Strikingly, oral treatment of infected hamsters with 100 mg/kg K11777 b.i.d. Combinations of either CPI with ABZ enhanced morbidity compared to single compounds. Both CPIs produced morbidity in ex vivo adult hookworms with the activity of K11777 again being at least the equivalent of ABZ. The reverse was true for K11777 with a larvicidal potency equal to that of the current anti-hookworm drug, albendazole (ABZ). In vitro, K11002 killed hookworm eggs but was without activity against first-stage larvae. The latter is in late pre-clinical testing for submission as an Investigational New Drug (IND) with the US Federal Drug Administration as an anti-chagasic. Using various life-cycle stages of the hookworm Ancylostoma ceylanicum in vitro and a hamster model of infection, we report the potent, dose-dependent cidal activities of the peptidyl cysteine protease inhibitors (CPIs) K11002 (4-mopholino-carbonyl-phenylalanyl-homophenylalanyl- vinyl sulfone phenyl) and K11777 ( N-methylpiperazine-phenylalanyl-homophenylalanyl-vinylsulfone phenyl).

Treat hookworms in humans