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Pharmaceuticals 2016, 9(3), 39; doi:10.3390/ph9030039

Odanacatib, a Cathepsin K Cysteine Protease Inhibitor, Kills Hookworm In Vivo

Center for Discovery and Innovation in Parasitic Diseases, Department of Pathology, University of California San Francisco, San Francisco, CA 94158, USA
Present address: Department of Biology and Biomedical Science, Salve Regina University, 100 Ochre Point Ave, Newport, RI 02840, USA
Present address: Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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Author to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 13 May 2016 / Revised: 30 June 2016 / Accepted: 30 June 2016 / Published: 4 July 2016
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Abstract

Hookworm infection is chief among soil-transmitted helminthiases (STHs) for the chronic morbidly inflicted. Deworming via mass drug administration (MDA) programs most often employs single doses of benzimidazole drugs to which resistance is a constant threat. To discover new drugs, we employ a hamster model of hookworm infection with Ancylostoma ceylanicum and use albendazole (ABZ; 10 mg/kg orally) as the gold standard therapy. We previously showed that a single oral 100 mg/kg dose of the cathepsin cysteine protease (CP) inhibitor, K11777, offers near cure of infection that is associated with a 95% reduction in the parasite’s resident CP activity. We confirm these findings here and demonstrate that odanacatib (ODN), Merck’s cathepsin K inhibitor and post-clinical Phase III drug candidate for treatment of osteoporosis, decreases worm burden by 73% at the same dose with a 51% reduction in the parasite’s CP activity. Unlike K11777, ODN is a modest inhibitor of both mammalian cathepsin B and the predominant cathepsin B-like activity measureable in hookworm extracts. ODN’s somewhat unexpected efficacy, therefore, may be due to its excellent pharmacokinetic (PK) profile which allows for sustained plasma exposure and, possibly, sufficient perturbation of hookworm cathepsin B activity to be detrimental to survival. Accordingly, identifying a CP inhibitor(s) that combines the inhibition potency of K11777 and the PK attributes of ODN could lead to a drug that is effective at a lower dose. Achieving this would potentially provide an alternative or back-up to the current anti-hookworm drug, albendazole. View Full-Text
Keywords: parasite; hookworm; soil-transmitted helminth; cysteine protease; K11777; odanacatib; Merck; anthelmintic parasite; hookworm; soil-transmitted helminth; cysteine protease; K11777; odanacatib; Merck; anthelmintic
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Vermeire, J.J.; Suzuki, B.M.; Caffrey, C.R. Odanacatib, a Cathepsin K Cysteine Protease Inhibitor, Kills Hookworm In Vivo. Pharmaceuticals 2016, 9, 39.

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