Acyclic nucleoside phosphonates as inhibitors of <em>Trypanosoma cruzi</em> hypoxanthine-guanine  phosphoribosyltransferase — ASN Events
  1. Schedule
  2. Session Five - Poster Session A including Refreshments
  3. Acyclic nucleoside phosphonates as inhibitors of Trypanosoma cruzi hypoxanthine-guanine  phosphoribosyltransferase

Acyclic nucleoside phosphonates as inhibitors of Trypanosoma cruzi hypoxanthine-guanine  phosphoribosyltransferase (#123)

David Terán 1 , Dana Hocková 2 , Michal Česnek 2 , Zlatko Janeba 2 , Lieve M. J. Naesens 3 , Dianne T. Keough 1 , Luke W. Guddat 1
  1. The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD, Australia
  2. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nam. 2, CZ-166 10 Prague 6, Czech Republic
  3. Rega Institute for Medical Research, KU Leuven – University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium

Chagas disease is an important infectious disease in the world today affecting 16-18 million people [1], particularly in Latin American countries. The etiological agent for Chagas disease is the protozoan parasite Trypanosoma cruzi. There are two drugs (i.e. benznidazole and nirfurtimox) currently available for this disease but prolonged treatment can result in severe side-effects. Furthermore, increased resistance to these drugs is becoming a serious threat to their continued viability [2]. Thus, new anti-Chagas chemotherapeutics are required. A potential target is the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRT), whose function appears to be critical to the life-cycle of this parasite [3]. A series of compounds, the acyclic nucleoside phosphonates (ANPs), have been tested as inhibitors of this enzyme with the most potent having a Ki value of 40 nM [4]. Computational docking of these compounds into the active site of the crystal structure of T. cruzi HGPRT have suggested the most likely mode of binding for these compounds.

  1. Nuñes, M. C., Dones, W., Morillo, C. A., Encina, J. J., & Ribeiro, A. L. (2013). Chagas disease: an overview of clinical and epidemiological aspects. J Am Coll Cardiol, 62(9), 767-776.
  2. Chatelain, E. (2014). Chagas Disease Drug Discovery: Toward a New Era. J Biomol Screen. doi: 10-1117.
  3. Santos, A. L., Branquinha, M. H., M., d’ Avila-Levy, C. L., Kneipp, L. F., & Sodre, C. L. (2014). Proteins and Proteomics of Leishmania and Trypanosoma. Springer Dordrecht Heidelberg, 1(1).
  4. Cesnek, M., Hockova, D., Holy, A., Dracinsky, M., Baszczynski, O., de Jersey, J., Dianne T. K., Guddat, L. W. (2012). Synthesis of 9-phosphonoalkyl and 9-phosphonoalkoxyalkyl purines: evaluation of their ability to act as inhibitors of Plasmodium falciparum, Plasmodium vivax and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases. Bioorg Med Chem, 20(2), 1076-1089.