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

Jon Vermeire,Brian Suzuki,Conor Caffrey

doi:10.3390/ph9030039

Jon Vermeire, Brian Suzuki + Show 1 more

Open Access

https://doi.org/10.3390/ph9030039

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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.

Highlights

Soil-transmitted helminthiases (STHs) caused by parasitic nematodes are associated with extreme poverty
The disease is primarily due to infection by Ancylostoma duodenale or Necator americanus, and is manifested in the under-nourished, causing or exacerbating iron-deficient anemia that can slow childhood physical development and cognition [5,6,7]
The smaller reduction in specific protease activity in worms exposed in vivo to ODN (51% vs. 96% for K11777) is consistent with the inhibitor’s weaker, but still considerable, anti-parasite efficacy (73% vs. 100% for K11777)

Summary

Introduction

Soil-transmitted helminthiases (STHs) caused by parasitic nematodes are associated with extreme poverty. The many attractive PK features of ODN include its low systemic clearance, long plasma half-life (T1/2) and good oral bioavailability (%F) in various pre-clinical animal models which conceivable would provide a sustained plasma loading to generate an anti-parasite effect (Table 2) In these same metrics, K11777, at a 20 to 50 times the dose in rats and dogs, respectively, was noticeably poorer. If PK is a key contributor to anti-hookworm efficacy, one might improve bioactivity by identifying small molecules that combine the nanomolar inhibition of the target cathepsin B proteases, as shown for K11777, with the attractive PK features of ODN. Within the framework of designing an improved inhibitor, possible safety concerns regarding off-targeting of orthologous host proteases can be addressed, mitigated by the knowledge that (i) treatment of hookworm infection will involve acute (single-dose) therapy only and (ii) the non-specific cathepsin inhibitor, K11777, continues to meet safety criteria as it progresses pre-clinically as a treatment for Chagas disease

Animals and Compounds

Treatment Regimens and Cysteine Protease Activity Assay

Findings

Conclusions