2458
J. Bower et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2455–2458
Table 2. Inhibition of E. coli in vitro protein translation (EcIVT)14
ribosomal RNA and generated rationally designed
ligands which have been shown to interact selectively
with the desired region. With the recent appearance of
high-resolution crystal structures ofthe prokaryotic
ribosome,15ꢀ17 we are confident that this integrated
approach will herald a new era in anti-infective
research, generating a variety ofnovel antibacterial
agents with strong clinical potential.
and antibacterial activity (MIC95
Compd
)
% EcIVT
inhibition
MIC95
Scaffold
Amine
Thiostrepton 1
98 (0.1)
—
48
—
31
0.015
>200
>200
>200
>200
>200
8
3
6
2
3
e
g
(OH)
n
n
16
References and Notes
EcIVT percentage inhibition measured at 200 mM. Figures in par-
entheses represent IC50 in mM.
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Conclusions
These studies have yielded a number ofnovel ligands
that have been shown to interact specifically with a vital
functional region of the bacterial ribosome and inhibit
protein translation. In conjunction with our earlier
4
results elucidating the structure ofthis key region, the
work described here is the first reported example of
rational, structure-based drug design targeted toward
this complex but vital cellular machine. Employing
computational techniques, NMR, molecular biology,
biochemistry and medicinal chemistry in a unified man-
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