title: Mining a cathepsin inhibitor library for new antiparasitic drug leads.
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.
authors.affiliation: The Small Molecule Discovery Center, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Kenny K H
authors.initials: KK
authors.lastname: Ang
authors.forename: Joseline
authors.initials: J
authors.lastname: Ratnam
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Jennifer
authors.initials: J
authors.lastname: Legac
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hansell
authors.forename: Zachary B
authors.initials: ZB
authors.lastname: Mackey
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Skrzypczynska
authors.forename: Anjan
authors.initials: A
authors.lastname: Debnath
authors.forename: Juan C
authors.initials: JC
authors.lastname: Engel
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
mesh_terms: D000977:Antiparasitic Agents / Q000302:isolation & purification* / Q000378:metabolism*; D057056:Cysteine Proteases / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D011480:Protease Inhibitors / Q000302:isolation & purification* / Q000378:metabolism*; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000977:Antiparasitic Agents; D011480:Protease Inhibitors; D057056:Cysteine Proteases