title: Novel cruzain inhibitors for the treatment of Chagas' disease.
abstract: The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas' disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T. cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas' disease.
authors.affiliation: Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, 92093, USA. krogers@ucsd.edu
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Rogers
authors.forename: Henrik
authors.initials: H
authors.lastname: Keränen
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Durrant
authors.forename: Joseline
authors.initials: J
authors.lastname: Ratnam
authors.forename: Allison
authors.initials: A
authors.lastname: Doak
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi