6-oxopurine phosphoribosyltransferase as an antimalarial drug target

LW Guddat1, DT Keough1, L Naesens2, M Chavchich3, M Edstein3, D Rejman4 and D Hockova4

  1. The School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane 4072, Queensland Australia
  2. Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
  3. Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland 4051, Australia
  4. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nám
  5. , CZ-166 10 Prague 6, Czech Republic

6-Oxopurine phosphoribosyltransferase catalyzes the formation of the 6-oxopurine nucleoside monophosphates from a purine base and 5′-phospho-α-D-ribosyl-1-pyrophosphate. A divalent metal ion is required for the reaction to proceed. This enzyme has been identified as an important target for antimalarial chemotherapy because it is their only pathway for the synthesis of the purine nucleoside monophosphates required for DNA/RNA production. Thus, inhibition of this enzyme should result in killing of the malarial parasite [1]. It has previously been shown that acyclic nucleoside phosphonates (ANPs) have been successfully developed as antiviral agents by targeting DNA polymerases and reverse transcriptases [2]. We have used rational structure-based drug design, including X-ray crystal structures, to propose new ANPs that we have subsequently synthesized. These new compounds are excellent inhibitors of Plasmodium falciparum HGXPRT, with Ki values as low as 0.08 and 0.01 µM for Plasmodium vivax HGPRT [3-5]. We have also developed prodrugs of these ANPs that exhibit antimalarial activity against Pf lines with IC50 values as low as 0.8 µM. These compounds have low cytotoxicity against human cells [4, 6].
References: [1] de Jersey et al., & Guddat, Curr Top Med Chem, 11 (2011) 2085. [2] De Clercq, Holý, Nat Rev Drug Discov, 4 (2005) 928. [3] Keough et al., & Guddat, J Med Chem, 52 (2009) 4391. [4] Keough et al, & Guddat, J Med Chem, 58 (2015) 827. [5] Keough et al., & Guddat, J Med Chem, 56 (2013) 2513-2526. [6] Hockova, et al., & Guddat, Bioorg Med Chem, 23 (2015) 5502.