 |
|
Title
|
|
Uracil-directed ligand tethering: an efficient strategy for uracil DNA glycosylase (UNG) inhibitor development.
|
|
|
Authors
|
|
Y.L.Jiang,
D.J.Krosky,
L.Seiple,
J.T.Stivers.
|
|
|
Ref.
|
|
J Am Chem Soc, 2005,
127,
17412-17420.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Uracil DNA glycosylase (UNG) is an important DNA repair enzyme that recognizes
and excises uracil bases in DNA using an extrahelical recognition mechanism. It
is emerging as a desirable target for small-molecule inhibitors given its key
role in a wide range of biological processes including the generation of
antibody diversity, DNA replication in a number of viruses, and the formation of
DNA strand breaks during anticancer drug therapy. To accelerate the discovery of
inhibitors of UNG we have developed a uracil-directed ligand tethering strategy.
In this efficient approach, a uracil aldehyde ligand is tethered via
alkyloxyamine linker chemistry to a diverse array of aldehyde binding elements.
Thus, the mechanism of extrahelical recognition of the uracil ligand is
exploited to target the UNG active site, and alkyloxyamine linker tethering is
used to randomly explore peripheral binding pockets. Since no compound
purification is required, this approach rapidly identified the first
small-molecule inhibitors of human UNG with micromolar to submicromolar binding
affinities. In a surprising result, these uracil-based ligands are found not
only to bind to the active site but also to bind to a second uncompetitive site.
The weaker uncompetitive site suggests the existence of a transient binding site
for uracil during the multistep extrahelical recognition mechanism. This very
general inhibitor design strategy can be easily adapted to target other enzymes
that recognize nucleobases, including other DNA repair enzymes that recognize
other types of extrahelical DNA bases.
|
|
|
|