 |
PDBsum entry 3i06
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Identification and optimization of inhibitors of trypanosomal cysteine proteases: cruzain, Rhodesain, And tbcatb.
|
|
|
Authors
|
|
B.T.Mott,
R.S.Ferreira,
A.Simeonov,
A.Jadhav,
K.K.Ang,
W.Leister,
M.Shen,
J.T.Silveira,
P.S.Doyle,
M.R.Arkin,
J.H.Mckerrow,
J.Inglese,
C.P.Austin,
C.J.Thomas,
B.K.Shoichet,
D.J.Maloney.
|
|
|
Ref.
|
|
J Med Chem, 2010,
53,
52-60.
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
