cure of hookworm infection with a cysteine protease inhibitor半胱氨酸蛋白酶抑制剂治疗钩虫感染.pdfVIP

Cure of Hookworm Infection with a Cysteine Protease Inhibitor 1 1 2 Jon J. Vermeire , Lorine D. Lantz , Conor R. Caffrey * 1 Department of Pediatrics, Section of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut, 2 Sandler Center for Drug Discovery, California Institute for Quantitative Biosciences and the Department of Pathology, University of California, San Francisco, San Francisco, California Abstract Background: Hookworm disease is a major global health problem and principal among a number of soil-transmitted helminthiases (STHs) 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. New chemical entities with the appropriate single-dose efficacy are needed. Methods and Findings: 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). 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. In vitro, K11002 killed hookworm eggs but was without activity against first-stage larvae. The reverse was true for K11777 with a larvicidal potency equal to that of the current anti-hookworm drug, albendazole (ABZ). Both CPIs produced morbidity in e