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TbVSP1 and L. major FPPS enzymes, only 19 had
measurable activity in both assays, but the overall
correlation between the two data sets was only R2 )
0.095. More significantly, of the three compounds (1, 2,
4) providing some protection against death, the com-
pound most active in vivo (2) has no effect on FPPS
inhibition (IC50 > 100 µM), as also found with compound
4. In the case of 1, this compound has been reported to
be an inhibitor of a human FPPS,53 so it is certainly
possible that in this case, both FPPS and the TbVSP1
are inhibited in vivo, but this is clearly not the case for
2 (the most active compound in vivo) or for 4. Of the 13
compounds investigated in vivo, the three providing
protection against death are among the top four inhibi-
tors of TbVSP1. The compound most active in vivo (2)
also has a very high therapeutic index in vitro and is
not an inhibitor of FPPS. These results therefore
support the idea that the most active compounds in vivo
act, at least in part, by inhibiting TbVSP1, an enzyme
that is critical for osmoregulation and virulence in T.
brucei. Since TbVSP1 is absent in humans, this work
opens up a potential route to the development of novel
trypanocides.
Acknowledgment. This work was supported by the
U.S. Public Health Service (National Institutes of
Health Grant GM65307).
Supporting Information Available: Microanalytical data
for compounds 1, 3, 4, 6-13, 15, 16, 18-20, 22, 23, 25-28,
30-37, 41, 44, 45, 48-51, 53, 55, 58-60, 62-66, 68, 73, 75-
1
79, and 81 and H and 31P NMR spectra for compounds 1-5.
(19) Montalvetti, A.; Bailey, B. N.; Martin, M. B.; Severin, G. W.;
Oldfield, E.; Docampo, R. Bisphosphonates are potent inhibitors
of Trypanosoma cruzi farnesyl pyrophosphate synthase. J. Biol.
Chem. 2001, 276, 33930-33937.
This material is available free of charge via the Internet at
(20) Lemercier, G.; Espiau, B.; Ruiz, F. A.; Vieira, M.; Luo, S.; Baltz,
T.; Docampo, R.; Bakalara, N. A pyrophosphatase regulating
polyphosphate metabolism in acidocalcisomes is essential for
Trypanosoma brucei virulence in mice. J. Biol. Chem. 2004, 279,
3420-3425.
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