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Five Orders of Magnitude Affinity Gain in Anti-trypanosomal Drug Development by Structure-based Design

Verlinde, C.L.M.J. (Biomolecular Structure Center & Dept. of Biological Structure, University of Washington, USA)

Contact Person: Christophe L M J Verlinde (verlinde@gouda.bmsc.washington.edu)


African trypanosomes derive all of their energy from glycolysis when in the human host, in their so-called bloodstream form. Hence, inhibiting their glycolytic enzymes may be a promising way to arrive at novel anti-trypanosomatid drugs provided that sufficient host versus guest selectivity can be obtained. Guided by the crystal structures of human and Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as well as the related Leishmania mexicana GAPDH, we designed adenosine derivatives that successfully compete out the parasite's enzyme cofactor NAD and have no such effect on the human enzyme. Adenosine was chosen as a lead compound. It inhibits both parasite and human GAPDH very weakly at ~50 mM, but provides the opportunity to reach a cleft which only exists on the parasite enzyme surface. Thus, by replacing the adenosine ribosyl's 2'-hydroxyl with a 2'-benzamido group selectivivity was obtained. Subsequently, extra affinity was achieved with an appropriate N6-substituent designed to fit in a nearby hydrophobic slot. The resulting compound 2'-deoxy-2'-(3-methoxybenzamido)-N6-(1-naphthalenemethyl)adenosine was shown to be a competitive inhibitor with respect to NAD of T. brucei GAPDH and L. mexicana GAPDH with IC50 values of 2 µM and 200 nM, respectively. This compound does not affect human GAPDH at concentrations up to 0.05 M. In vitro it blocks the growth of bloodstream form T. brucei with an ED50 of about 30 µM and appears to be harmless to mammalian cells at concentrations up to 0.05 mM.

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Poster Number PAverlinde0900
Keywords: design, glycolysis, inhibitor, modeling, trypanosomiasis

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Verlinde, C.L.M.J.; (1998). Five Orders of Magnitude Affinity Gain in Anti-trypanosomal Drug Development by Structure-based Design. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/pharmtox/verlinde0900/index.html
© 1998 Author(s) Hold Copyright