LAUSR

As noted in the introductory review, cysteine proteases are attractive targets for structurebased drug design because of their well-defined active site topology and mechanism of action, available high-throughput assays, and known drugability. Drugs targeting human cysteine proteases, homologous to those found in parasitic organisms, entered clinical trials as drug candidates for the treatment of psoriasis, osteoporosis, autoimmune diseases, and cancer. Specific cysteine proteases targeted by the pharmaceutical industry for drug development include cathepsin S, cathepsin K, and cathepsin B. Some of these development efforts are ongoing, others (e.g., Odanacatib) were halted for efficacy or toxicology reasons. Conversely, a number of chemical scaffolds and “warheads” have been evaluated as inhibitors of parasite cysteine protease targets [1]. While effective at the biochemical and cellular level, most of these were subsequently abandoned for efficacy or safety issues. Vinyl sulfones and nitriles, the focus of this update, remain viable after preclinical screens. One can envision 2 approaches for targeting diseases caused by parasites. The first is the direct repurposing of drugs, developed and approved for treatment of host diseases against parasitic infections. Efforts to repurpose drugs developed against diseases thought to involve human cathepsin S are following this strategy. Safety is paramount, but failure of efficacy against a host disease is not always relevant. The second approach focuses on specific active site-directed “warheads,” already proven efficacious for targeting other disease processes involving homologous cysteine proteases. An example of this approach is the exploration of nitrile derivatives (Fig 1) developed for osteoporosis as drugs to treat Chagas disease [2]. Nitrile-derivatized inhibitor scaffolds, while inhibiting cysteine proteases in a mechanism-based manner, are considered “reversible,” although often with slow off rates. Indeed, compounds that were abandoned early in the drug development process for failure to ameliorate a host disease may still have efficacy versus parasitic infections. An example is the “proof of concept” vinyl sulfone inhibitor K777 (also known as K 11777). This compound (Fig 1) was originally developed as an inhibitor of human cathepsin S by scientists at Khepri Pharmaceuticals [3]. K777 was effective in animal models of Chagas disease, schistosomiasis, hookworm infection, and cryptosporidiosis (referenced elsewhere in this PLOS NTDs collection). It may very well have other uses yet to be defined. Based upon its efficacy against the cysteine protease (cruzain, also known as cruzipain) of Trypanosoma cruzi, this inhibitor underwent extensive preclinical testing at several Contract Research Organizations (CROs). Key studies are summarized in Table 1. Importantly, the cysteine protease inhibitor was found to be safe in rodents, dogs, and nonhuman primates. Safety testing included 7-, 14-, and 28-day chronic dosing. In addition, specific metabolites of this compound were identified in mammals.