Two approaches to discovering and developing new drugs for Chagas disease

Abstract

This review will focus on two general approaches carried out at the Sandler Center, University of California, San Francisco, to address the challenge of developing new drugs for the treatment of Chagas disease. The first approach is target-based drug discovery, and two specific targets, cytochrome P450 CYP51 and cruzain (aka cruzipain), are discussed. A “proof of concept” molecule, the vinyl sulfone inhibitor K777, is now a clinical candidate. The preclinical assessment compliance for filing as an Investigational New Drug with the United States Food and Drug Administration (FDA) is presented, and an outline of potential clinical trials is given. The second approach to identifying new drug leads is parasite phenotypic screens in culture. The development of an assay allowing high throughput screening of Trypanosoma cruzi amastigotes in skeletal muscle cells is presented. This screen has the advantage of not requiring specific strains of parasites, so it could be used with field isolates, drug resistant strains or laboratory strains. It is optimized for robotic liquid handling and has been validated through a screen of a library of FDA-approved drugs identifying 65 hits.

In vitro and in vivo experimental models for drug screening and development for Chagas disease

“…However, when other automated or alternative screening systems become available, such as the one reported by McKerrow et al (2009), it is highly recommended that this protocol be changed to include parasite stocks from different geographical regions and stocks with known resistance to Bz and nifurtimox that belong to the six discrete typing units -T. cruzi I-VI (Zingales et al 2009). …”

Biological Roles of Peptidases in Trypanosomatids~!2009-11-26~!2010-02-15~!2010-03-18~!

“…Furthermore, these enzymes are considered virulence factors [52,53]. Therefore, they are promising targets for the design of antimicrobials against trypanosomatid diseases [39][40][41]55]. In addition, the ability of lower trypanosomatids to express homologues of Leishmania and Trypanosoma virulence factors seems to play essential roles in the nutrition as well as in the interaction with the insect epithelial cells.…”

“…cruzain is found on the surface of the parasite, directly in contact with host cell cytoplasm [65,41].…”

“…Currently, a cruzipain inhibitor, the vinyl sulfone K777 has entered in preclinical drug development investigations [41].…”

“…Moreover, in addition to serious side effects, resistance against both compounds leads to increasing treatment failures [40]. Within this framework, an intense research program has been directed to develop strategies to produce a vaccine or efficient non-toxic drugs, through the investigation of specific targets such as molecules, organelles and metabolic pathways in T. cruzi [41].…”