2. Academic Validation
  3. Stereo-Defined Acyclic Nucleoside Phosphonates are Selective and Potent Inhibitors of Parasite 6-Oxopurine Phosphoribosyltransferases

Stereo-Defined Acyclic Nucleoside Phosphonates are Selective and Potent Inhibitors of Parasite 6-Oxopurine Phosphoribosyltransferases

  • J Med Chem. 2022 Mar 10;65(5):4030-4057. doi: 10.1021/acs.jmedchem.1c01881.
Tomáš Klejch 1,  Dianne T Keough 2,  Gordon King 3,  Eva Doleželová 4,  Michal Česnek 1,  Miloš Buděšínský 1,  Alena Zíková 4 5,  Zlatko Janeba 1,  Luke W Guddat 2,  Dana Hocková 1
Affiliations

Affiliations

  • 1 The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 6 CZ-16000, Czech Republic.
  • 2 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Australia.
  • 3 The Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane 4072, Australia.
  • 4 Institute of Parasitology, Biology Centre ASCR, České Budějovice 37005, Czech Republic.
  • 5 Faculty of Science, University of South Bohemia, České Budějovice 37005, Czech Republic.
PMID: 35175749 DOI: 10.1021/acs.jmedchem.1c01881
Abstract

Pathogens such as Plasmodium and Trypanosoma spp. are unable to synthesize purine nucleobases. They rely on the salvage of these purines and their nucleosides from the host cell to synthesize the purine nucleotides required for DNA/RNA production. The key Enzymes in this pathway are purine phosphoribosyltransferases (PRTs). Here, we synthesized 16 novel acyclic nucleoside phosphonates, 12 with a chiral center at C-2', and eight bearing a second chiral center at C-6'. Of these, bisphosphonate (S,S)-48 is the most potent inhibitor of the Plasmodium falciparum and P. vivax 6-oxopurine PRTs and the most potent inhibitor of two Trypanosoma brucei (Tbr) 6-oxopurine PRTs yet discovered, with Ki values as low as 2 nM. Crystal structures of (S,S)-48 in complex with human and Tbr 6-oxopurine PRTs show that the inhibitor binds to the Enzymes in different conformations, providing an explanation for its potency and selectivity (i.e., 35-fold in favor of the Parasite enzymes).

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