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- Title
Mining a Cathepsin Inhibitor Library for New Antiparasitic Drug Leads.
- Authors
Ang, Kenny K. H.; Ratnam, Joseline; Gut, Jiri; Legac, Jennifer; Hansell, Elizabeth; Mackey, Zachary B.; Skrzypczynska, Katarzyna M.; Debnath, Anjan; Engel, Juan C.; Rosenthal, Philip J.; McKerrow, James H.; Arkin, Michelle R.; Renslo, Adam R.
- Abstract
The targeting of parasite cysteine proteases with small molecules is emerging as a possible approach to treat tropical parasitic diseases such as sleeping sickness, Chagas' disease, and malaria. The homology of parasite cysteine proteases to the human cathepsins suggests that inhibitors originally developed for the latter may be a source of promising lead compounds for the former. We describe here the screening of a unique ∼2,100-member cathepsin inhibitor library against five parasite cysteine proteases thought to be relevant in tropical parasitic diseases. Compounds active against parasite enzymes were subsequently screened against cultured Plasmodium falciparum, Trypanosoma brucei brucei and/or Trypanosoma cruzi parasites and evaluated for cytotoxicity to mammalian cells. The end products of this effort include the identification of sub-micromolar cell-active leads as well as the elucidation of structure-activity trends that can guide further optimization efforts. Author Summary: Diseases like malaria and sleeping sickness are caused by tropical parasites and represent a major cause of mortality and morbidity in the developing world. A pragmatic approach to discover new drugs for these diseases is to search for drug leads among existing small molecule collections generated in the for-profit pharmaceutical industry. In this study, we searched for new drug leads among a collection of small molecules donated by Celera Genomics. This collection of molecules was originally developed to inhibit a class of human enzymes (cathepsins) implicated in diseases like osteoporosis and psoriasis. Similar enzymes are also present in most tropical parasites, making this collection a logical place to search for new drug leads. The end result of this effort saw the identification of compounds that inhibit the growth of one or more tropical parasites and that will serve as good starting points for the development of new drugs for tropical parasitic diseases.
- Subjects
CHAGAS' disease; CYSTEINE proteinases; DEVELOPING countries; ANTIPARASITIC agents; PARASITIC diseases; SMALL molecules
- Publication
PLoS Neglected Tropical Diseases, 2011, Vol 5, Issue 5, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0001023