Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB.
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.
Mott
Bryan T
BT
NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, MSC 3370 Bethesda, Maryland 20892-3370, USA.
Ferreira
Rafaela S
RS
Simeonov
Anton
A
Jadhav
Ajit
A
Ang
Kenny Kean-Hooi
KK
Leister
William
W
Shen
Min
M
Silveira
Julia T
JT
Doyle
Patricia S
PS
Arkin
Michelle R
MR
McKerrow
James H
JH
Inglese
James
J
Austin
Christopher P
CP
Thomas
Craig J
CJ
Shoichet
Brian K
BK
Maloney
David J
DJ
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
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