Abstract Hookworm disease affects 10% of the world's population yet treatment relies on monotherapy using just one class of drugs, the benzimidazoles. Resistance to these drugs is ubiquitous in the animal health sector and is of growing concern in the human arena. The PI has discovered that a cysteine protease inhibitor (CPI), K11777, cures hookworm infection (Ancylostoma ceylanicum) in a hamster model at a single oral dose of 100 mg/kg. Consistent with the inhibitor's known mechanism of action, K11777 inhibits by >90% the cathepsin B cysteine protease activity resident in the parasite's gut. In studies chaperoned by the PI's research institution, K11777 has already advanced through efficacy and toxicological testing in rodent, dog and monkey models as a drug candidate for sub-acute (30-day dosing) treatment of Chagas' disease. The data generated in these studies suggest that a therapeutic window exists for treatment of hookworm in the single oral dose mandated for mass drug administration of de-worming agents. However, K11177's potency in the hamster is less than that of the current drug, albendazole, potentially limiting the inhibitor's competitiveness. Therefore, as alternatives, we have identified a small set of chemically diverse CPIs from recent drug discovery projects for Chagas' disease at the PI's research center. The available data regarding inhibition potency, in vitro metabolism and/or in vivo pharmacokinetics (PK) suggest that one or more of these inhibitors should cure hookworm in hamsters at lower doses than K11777. Three Aims are proposed: (1) synthesize and test CPIs advancing in other drug discovery programs for the lowest dose necessary to cure hamsters of hookworm; (2) determine the relative potency of synthesized CPIs against hookworm cathepsins B and (3) characterize the in vivo pharmacokinetics of CPIs at the lowest dose needed to cure infection in hamsters. The aims will provide comprehensive data associating dose, on-target potency and plasma exposure with cure of infection in the hamster. Data for drug plasma exposure will help scale the dosing required to assure therapeutic plasma levels in the final, pre-clinical dog model of hookworm infection. The exit point from this exploratory project is at least one candidate to take into efficacy testing in the dog model of hookworm infection.