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Document for human GAPDH is better than for the parasite enzymes, namely 35 mM [13]. Despite the fact that these IC 50 values are about ten thousand times higher than what would be considered a lead in the pharmaceutical industry we decided to optimize the affinity and selectivity of adenosine. Page 385 Each of the three areas where differences occur between the parasite and the human enzyme are hydrophobic. Therefore, we modeled hydrophobic substituents at positions C2, C8, and O2' of adenosine under the constraint that they were conformationally compatible with the C2'-endo pucker of the ribose sugar. Designing derivatives at O2' was a problem, however. Each of the two ribosyl hydroxyls forms a hydrogen bond with the carboxylate of Asp37. Since making direct derivatives of the hydroxyl, such as ethers or esters, would deprive the Asp of a hydrogen-bond partner while burying the carboxylate, resulting molecules would have a dramatically reduced affinity. Moreover, an alignment of 47 GAPDH sequences made it clear that the Asp is highly conserved [89]. An elegant way to overcome this problem was to replace the 2' -hydroxyl by a 2'- amino function. Moreover, coupling with carboxylic acids was appealing from a synthetic point of view while the conformational properties of the amido-substituted system would ensure the correct orientation of substituents into the selectivity cleft. The modeled inhibitors were evaluated for the quality of their fit to the protein surface and subsequently synthesized. From Table 8 it can be seen that our predictions were successful. The addition of a methyl group at C2 of the adenine ring, which is close to Val36, increased the affinity for parasite GAPDH by an order of magnitude. The effect of a thienyl substitution on C8, targeted to Leu112, was even bigger, namely two orders of magnitude. However, both substitutions are only mildly selective (Table 8). As expected, the greatest gain in selectivity was obtained by modifying the 2'-position of the ribose, so that the selectivity cleft is filled up (Figure 12). The 2'-deoxy-2'-(3-methoxybenzamido) adenosine compound (Figure 13) bound at least 48 times better to L. mexicana GAPDH than to the human enzyme. The selectivity versus T. brucei GAPDH appeared to be smaller. This has to be ascribed to a difference in residues contacting the 3-methoxy moeity. The residue Asn39 of T. brucei GAPDH has a Ser equivalent in the L. mexicana Table 8 Inhibition Gains of Designed GAPDH Inhibitors with Respect to Adenosine C2-subst C8-subst C2'-subst T. brucei L. mexicana human CH 3 H OH 12.5 6.25
Document Figure 12 Predicted binding mode of 2' -deoxy-2'-(3-methoxybenzamido)adenosine to T.brucei GAPDH. (From Ref. 13. Copyright 1994 by the American Chemical Society.) enzyme. In conclusion, the strategy of burying hydrophobic residues with lipophilic substituents paid off. Page 386 Despite the rather poor IC 50 values of our optimized inhibitors, an evaluation of their effect on live trypanosomes appeared to be useful. Enzyme inhibitors that are not taken up by the parasites would be of no use as a drug. Therefore, the effect of 2-methyl-adenosine, 8-(thien-2-yl)-adenosine and 2'- deoxy- 2'-(3-methoxybenzamido)adenosine on the growth of T. brucei in cultures, as described by Baltz et al. [90], was monitored. At 0.1 mM all compounds inhibited the growth completely, unlike adenosine derivatives that were without inhibitory effect against T. brucei GAPDH [91]. Experiments are underway to confirm that the growth inhibition is due to blockage of the glycolytic pathway. Also, te mechanism of uptake of te inhibitors will be examined because it is now well established that trypanosomes possess a unique P 2 purine transporter that they use for uptake of purines from the host [15]. The experimental antitrypanosomal drug 5'-{[(Z)-4-amino-2-butenyl}methylamino}-5'deoxyadenosine(MDL 73811) Figure 13), which is an irreversible S- adenosyl-L-methionine decarboxylase inhibitor, is actively taken up through the P2 transporter. Moreover, MDL 73811 is not actively transported in the human host, which presumably contributes to the drug's selectivity [19]. It is not unthinkable that our inhibitors might use the same transporter because of the nature of their scaffold, adenosine. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_386.html (1 of 2) [4/5/2004 5:42:07 PM]
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