 |
PDBsum entry 1u9q
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Development of alpha-Keto-Based inhibitors of cruzain, A cysteine protease implicated in chagas disease.
|
|
|
Authors
|
|
Y.Choe,
L.S.Brinen,
M.S.Price,
J.C.Engel,
M.Lange,
C.Grisostomi,
S.G.Weston,
P.V.Pallai,
H.Cheng,
L.W.Hardy,
D.S.Hartsough,
M.Mcmakin,
R.F.Tilton,
C.M.Baldino,
C.S.Craik.
|
|
|
Ref.
|
|
Bioorg Med Chem Lett, 2005,
13,
2141-2156.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas
disease, a major cause of cardiovascular disease in many Latin American
countries. There is an urgent need to develop an improved therapy due to the
toxicity of existing drugs and emerging drug resistance. Cruzain, the primary
cysteine protease of T. cruzi, is essential for the survival of the parasite in
host cells and therefore is an important target for the development of
inhibitors as potential therapeutics. A novel series of alpha-ketoamide-,
alpha-ketoacid-, alpha-ketoester-, and aldehyde-based inhibitors of cruzain has
been developed. The inhibitors were identified by screening protease targeted
small molecule libraries and systematically optimizing the P1, P2, P3, and P1'
residues using specific structure-guided methods. A total of 20 compounds
displayed picomolar potency in in vitro assays and three inhibitors representing
different alpha-keto-based inhibitor scaffolds demonstrated anti-trypanosomal
activity in cell culture. A 2.3A crystallographic structure of cruzain bound
with one of the alpha-ketoester analogs is also reported. The structure and
kinetic assay data illustrate the covalent binding, reversible inhibition
mechanism of the inhibitor. Information on the compounds reported here will be
useful in the development of new lead compounds as potential therapeutic agents
for the treatment of Chagas disease and as biological probes to study the role
that cruzain plays in the pathology. This study also demonstrates the validity
of structure-guided approaches to focused library design and lead compound
optimization.
|
|
|
|
|
|
|
