We
describe a general
metho
d for the
mi
micry of one face of an
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>-helix base
d on a terphenylscaffol
d that spatially projects functionality in a
manner si
milar to that of two turns of an
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>-helix. The syntheticscaffol
d re
duces the flexibility an
d molecular weight of the
mi
micke
d protein secon
dary structure. We haveapplie
d this
design to the
develop
ment of antagonists of the
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>-helix bin
ding protein Bcl-x
L. Using a sequentialsynthetic strategy, we have prepare
d a library of terphenyl
derivatives to
mi
mic the helical region of theBak BH3
do
main that bin
ds Bcl-x
L. Fluorescence polarization assays were carrie
d out to evaluate the abilityof terphenyl
derivatives to
displace the Bcl-x
L-boun
d Bak pepti
de. Terphenyl
14 exhibite
d goo
d in vitroaffinity with a
Ki value of 0.114
![](/i<font color=)
mages/entities/
mgr.gif">M. These terphenyl
derivatives were
more selective at
disrupting theBcl-x
L/Bak over the HDM2/p53 interaction, which involves bin
ding of the N-ter
minal
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>-helix of p53 to HDM2.Structural stu
dies using NMR spectroscopy an
d co
mputer-ai
de
d docking si
mulations suggeste
d that thehelix bin
ding area on the surface of Bcl-x
L is the target for the synthetic ligan
ds. Treat
ment of hu
mane
mbryonic ki
dney 293 (HEK293) cells with terphenyl
derivatives resulte
d in the
disruption of the bin
ding ofBcl-x
L to Bax in intact cells.