Crystal structures of <em>Mycobacterium tuberculosis</em> hypoxanthine-guanine phosphoribosyltransferase: A new therapeutic drug target — ASN Events
  1. Schedule
  2. Session Five - Poster Session A including Refreshments
  3. Crystal structures of Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase: A new therapeutic drug target

Crystal structures of Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase: A new therapeutic drug target (#111)

Wai Soon Eng 1 , Dana Hocková 2 , Petr Špaček 2 , Zlatko Janeba 2 , Nick P. West 1 , Kyra Woods 1 , 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, QLD, Australia
  2. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic
  3. Rega Institute for Medical Research, KU Leuven – University of Leuven, Leuven, Belgium
Human tuberculosis is a chronic infectious disease affecting millions of lives every year. Because of emerging resistance to current medications, new therapeutic drug targets are urgently needed.1 One such target is hypoxanthine-guanine phosphoribosyltransferase (HGPRT), a key enzyme of the purine salvage pathway where it synthesizes the 6-oxopurine nucleoside monophosphates needed for DNA/RNA production. It was previously proposed that inhibition of this enzyme should arrest the growth of this pathogen.2 Further, the gene coding for HGPRT in Mycobacterium tuberculosis (Mt) has been shown to be essential for the survival of the bacteria confirming this enzyme as a potential chemotherapeutic target.3 Acyclic nucleoside phosphonates (ANPs), analogues of the nucleoside monophosphates, have been shown to inhibit the activity of other 6-oxopurine phoshoribosyltransfearse (PRTases).4; 5 New derivatives of the ANPs have now been synthesized and found to be competitive inhibitors of MtHGPRT with Ki values as low as 0.69 μM. As the structure of this enzyme was unknown, crystal structures of MtHGPRT in complex with three different ANPs as well as in complex with GMP.PPi, the two products of reaction, were obtained. This knowledge is being used to improve the potency of these compounds by rational drug design. The arrangement of the four subunits that form the active tetrameric structure differs from that of the human HGPRT, suggesting a different evolutionary pathway. This may have occurred as a protective mechanism to avoid proteolysis within the cell of a critical flexible loop, common to all the 6-oxopurine PRTases. Prodrugs of the ANPs, containing hydrophobic groups attached by a phosphoramidate bond, have been synthesized. They exhibit antituberculosis activity with MIC50 values of 4.5 μM in a virulent strain of M. tuberculosis (H37Rv) and also have low cytotoxicity in mammalian cells. These data support the proposition that inhibitors of MtHGPRT can be developed as antituberculosis agents.
  1. World Health Organization. (2012). Global Tuberculosis Report. http://www.who.int/tb/publications/global_report/en/. Accessed October 20, 2014.
  2. Keough, D. T., Hocková, D., Rejman, D., Špaček, P., Vrbková, S., Krečmerová, M., Eng, W. S., Jans, H., West, N. P., Naesens, L. M. J., de Jersey, J. & Guddat, L. W. (2013). Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: Potential for new antibacterial agents. J Med Chem 56, 6967-6984.
  3. Griffin, J. E., Gawronski, J. D., DeJesus, M. A., Ioerger, T. R., Akerley, B. J. & Sassetti, C. M. (2011). High-resolution phenotypic profiling defines genes essential for mycobacterial growth and cholesterol catabolism. Plos Pathog 7.
  4. Hocková, D., Keough, D. T., Janeba, Z., Wang, T.-H., de Jersey, J. & Guddat, L. W. (2012). Synthesis of novel N-branched acyclic nucleoside phosphonates as potent and selective inhibitors of human, Plasmodium falciparum and Plasmodium vivax 6-oxopurine phosphoribosyltransferases. J Med Chem 55, 6209-6223.
  5. Keough, D. T., Špaček, P., Hocková, D., Tichý, T., Vrbková, S., Slavětínská, L., Janeba, Z., Naesens, L., Edstein, M. D., Chavchich, M., Wang, T. H., de Jersey, J. & Guddat, L. W. (2013). Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity. J Med Chem 56, 2513-2526.