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Document Figure 13 Two-dimensional structures of 2'-deoxy-2'-(3-methoxybenzamido) adenosine (MMBA), a selective T.brucei GAPDH inhibitor and MDL 73811, an irreversible inhibitor of trypanosomal S-adenosyl methionine decarboxylase. Page 387 Finally, we want to point out that pessimism about adenosine derivatives as drugs is not necessarily warranted. This doubt stems from the argument that many proteins recognize NAD(P), adenosine, or ATP. Cross-reactivity of adenosine with these different proteins and, therefore, toxicity may be expected. That this is not necessarily so is evident from the use of adenosine derivatives as antileukemia agents. For example, fludarabine, a C2'-epimer of adenosine, exhibits relatively low toxicity [92]. The much bigger changes to the adenosine scaffold in our inhibitors may hence lead to a surprisingly high overall selectivity. V. Conclusions Our goal is to discover and design selective inhibitors of trypanosomal glycolsysis. Thusfar, three enzymes have been targeted. Whereas little success was obtained with TIM, substantial progress is being made with GAPDH and PGK. Obstacles encountered during this project were the need for selective inhibitors and the absence of potent inhibitors as lead compounds. From our studies to inhibit TIM it appears that it is difficult to come up with inhibitors for areas on the protein surface for which no known inhibitors exist. On the other hand, lead optimization for GAPDH by over two orders of magnitude in just one cycle of drug design was straightforward. Selectivity was obtained by using part of the cofactor as a lead and exploiting the hydrophobic patches at the surface of the parasite enzyme. In particular, 2'-deoxy-2' (3methoxy-benzamido)ade- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_387.html (1 of 2) [4/5/2004 5:42:15 PM]
Document Page 388 nosine proved to inhibit the parasite more than fifty times better than the human enzyme. Additionally, by means of the program DOCK, eight new leads for GAPDH inhibition were found. None of them were micromolar inhibitors but all of them were more potent than the natural lead, adenosine. For trypanosomal PGK a potent lead compound, SPADNS, was discovered by testing inhibitors that had been described as weak inhibitors of yeast PGK. Moreover, this lead had no effect on mammalian PGK at concentrations up to twenty-five times higher than that needed for T. brucei inhibition. At present, none of our inhibitors is potent enough to consider clinical tests. There is hope, however, since our GAPDH inhibitors inhibit the growth of trypanosomes in cultures. Acknowledgments It is a pleasure to thank the many colleagues and collaborators who have contributed to this project: Paul Michels, Veronique Hannaert, Sylvie Allert, and Linda Kohl (Institute for Cellular Pathology in Brussels) for cloning and overexpressing trypanosomatid enzymes; Phil Petra (University of Washington, Seattle) for helping us out with protein purification protocols; Mia Callens and Fred Opperdoes (Institute for Cellular Pathology in Brussels) for enzymology and parasitology; Rik Wierenga, Martin Noble, Fred Vellieux, Randy Read, Risto Lapatto, Hillie Groendijk, Tjaard Pijning, and Kor Kalk for laying the structural foundation of the project in Groningen and Heidelberg; Cees Witmans and the late Alan Horn (University of Groningen), Michèle Willson and Jacques Perié (University of Toulouse), Serge Van Calenbergh, Arthur Van Aerschot, and Piet Herdewijn (University of Leuven) for synthesizing TIM and GAPDH inhibitors; Kim Simons (University of Washington) for going after completely new GAPDH inhibitors; Véronique Mainfroid and Joseph Martial (University of Liège) for providing human TIM; Klaus Muml;uller and Klaus Gubernator (Hoffmann-La Roche, Basel) for valued modeling advice; and Mike Gelb (University of Washington) for valued discussions. Financial support for these investigations has been provided by the World Health Organization, Hoffmann-LaRoche in Basel, the Dutch Organization for the Advancement of Science (NWO), the STD program of the European Community, the School of Medicine of the University of Washington, and the Murdock Charitable Trust. Note Added in Proof We just solved the ternary structure of PGK from Trypanosoma brucei in complex with ADP and 3phosphoglycerate. The enzyme is in the closed conformation that has eluded crystallographers for 20 years. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_388.html [4/5/2004 5:42:18 PM]
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