title: Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB.
abstract: Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely on essential cysteine proteases for survival: cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles, which are known inhibitors of other cysteine proteases, as reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against a panel of human cysteine and serine proteases to determine selectivity, and a cocrystal was obtained of our most potent analogue bound to cruzain.
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, MSC 3370 Bethesda, Maryland 20892-3370, USA.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Mott
authors.forename: Rafaela S
authors.initials: RS
authors.lastname: Ferreira
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Kenny Kean-Hooi
authors.initials: KK
authors.lastname: Ang
authors.forename: William
authors.initials: W
authors.lastname: Leister
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Julia T
authors.initials: JT
authors.lastname: Silveira
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Doyle
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: James
authors.initials: J
authors.lastname: Inglese
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
mesh_terms: D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D011687:Purines; D014227:Triazines; D003546:Cysteine Endopeptidases; C533458:TbcatB protein, Trypanosoma brucei; C074032:cruzain, Trypanosoma cruzi; C446033:rhodesain; C030985:purine