Mining a cathepsin inhibitor library for new antiparasitic drug leads

• Published in: PLoS neglected tropical diseases Vol. 5; no. 5; p. e1023
• Main 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2011; Public Library of Science (PLoS)
• Subjects: Antiparasitic agents; Antiparasitic Agents - isolation & purification; Antiparasitic Agents - metabolism; Biology; Cathepsins; Chemistry; Cysteine Proteases - metabolism; Cytotoxicity; Disease; Drug Evaluation, Preclinical; Drug therapy; Health aspects; Library collections; Malaria; Mortality; Parasites; Parasitic diseases; Parasitic Sensitivity Tests; Pharmaceutical industry; Physiological aspects; Plasmodium falciparum; Plasmodium falciparum - drug effects; Protease Inhibitors - isolation & purification; Protease Inhibitors - metabolism; Risk factors; Tropical diseases; Trypanosoma brucei brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; United States; Plasmodium falciparum; Cysteine Proteases; Parasitic Sensitivity Tests; Protease Inhibitors; Drug Evaluation, Preclinical; Trypanosoma brucei brucei; Antiparasitic Agents; Trypanosoma cruzi
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0001023

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.