Angewandte
Chemie
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Figure 4. Superposition of the TROSY spectra of tRNALys3 alone
(0.3 mm; black) and tRNALys3 mixed with compound 17 f (0.3 mm;
red).
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[16] The use of this “target-observation” strategy (as opposed to
ligand-observation schemes, such as saturation transfer) is
essential to filter out promiscuous binders, which interact
through nonspecific electrostatic interactions with the highly
charged nucleic acid. Promiscuous binders cause a general
broadening of the NMR spectrum of the target, whereas specific
binders induce only peak shifts, which allow the identification of
the binding site. For a general review, see: H. O. Villar, J. Yan,
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[18] Not surprisingly, the aminoglycosides neomycin and kanamycin
were also detected as tRNALys3 ligands. However, they are too
complex for a fragment-based approach. In contrast, compound
1 is an excellent 2-deoxystreptamine surrogate in the design of
“RNA-friendly” compounds: L. Micouin, F. P. Dardel, C. Tisne-
Vicrobeck, F. Maurice, M. Bonin, A. Perez Luna, C. J. Bour-
naud, G. BØgis, WO2006024784, 2006.
Table 1: Dissociation constants Kd [mm] of compound 17 f for three
different tRNA molecules at various ionic strengths.
tRNALys3
tRNAfMet
tRNAm
Met
KCl (150 mm)
KCl (50 mm)
no KCl
1.8Æ0.9
1.1Æ0.3
0.3Æ0.1
13.2Æ5.9
2.5Æ0.8
–
4.1Æ0.9
1.1Æ0.2
–
first time. This study outlines the power of a fragment-based
strategy in the field of RNA-ligand discovery, providing
potential lead compounds for the development of antiviral
drugs. The use of compound 17 f as an inhibitor of reverse
transcription in cell-free assays will be investigated. Besides
this important application, this study provides newinforma-
tion on the design of small RNA-interacting molecules. This
step is crucial for achieving a challenging goal: cellular
regulation at the RNA level by small-molecule effectors.
Received: December 22, 2006
Revised: March 13, 2007
Published online: May 7, 2007
[19] a) S. Yoshizawa, D. Fourmy, R. G. Eason, J. D. Puglisi, Biochem-
istry 2002, 41, 6263 – 6270; see also reference [7].
Keywords: aminoglycoside mimics · drug design ·
[20] Both enantiomerically enriched (e.r. = 93/7) isomers of com-
pound 17 f were prepared. The dissociation constant Kd = (1.2 Æ
0.6) mm was found for (R)-17 f with tRNALys3 at an ionic strength
of 150 mm KCl, and Kd = (1.1 Æ 0.7) mm was found for (S)-17 f
under the same conditions. Thus, the interaction with tRNALys3 is
not stereospecific, and racemic ligands can be used in this
approach. For the enantioselective preparation of 1, see: a) A.
PØrez Luna, M.-A. Ceschi, M. Bonin, L. Micouin, H.-P. Husson,
S. Gougeon, G. Estenne Bouthou, B. Marabout, M. Sevrin, P.
George, J. Org. Chem. 2002, 67, 3522 – 3524; b) A. PØrez Luna,
M. Bonin, L. Micouin, H.-P. Husson, J. Am. Chem. Soc. 2002,
124, 12098 – 12099.
.
fragment-based synthesis · RNA recognition · tRNA
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Angew. Chem. Int. Ed. 2007, 46, 4489 –4491
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4491