Acyclic immucillin phosphonates: Second-generation inhibitors of plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

Keith Z. Hazleton, Meng Chiao Ho, Maria B. Cassera, Keith Clinch, Douglas R. Crump, Irving Rosario, Emilio F. Merino, Steven C. Almo, Peter C. Tyler, Vern L. Schramm

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Plasmodium falciparum, the primary cause of deaths from malaria, is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine- xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5′-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. Here, we present a class of HGXPRT inhibitors, the acyclic immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective, and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria.

Original languageEnglish (US)
Pages (from-to)721-730
Number of pages10
JournalChemistry and Biology
Volume19
Issue number6
DOIs
StatePublished - Jun 22 2012

Fingerprint

Organophosphonates
Hypoxanthine
Plasmodium falciparum
Salvaging
Parasites
Prodrugs
Malaria
Purine-Nucleoside Phosphorylase
Purine Nucleotides
Inosine Monophosphate
Inosine
Antimalarials
Starvation
Cell culture
Haplorhini
Cause of Death
Nucleotides
Cell Culture Techniques
hypoxanthine-guanine-xanthine phosphoribosyltransferase
Infection

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

Cite this

Acyclic immucillin phosphonates : Second-generation inhibitors of plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase. / Hazleton, Keith Z.; Ho, Meng Chiao; Cassera, Maria B.; Clinch, Keith; Crump, Douglas R.; Rosario, Irving; Merino, Emilio F.; Almo, Steven C.; Tyler, Peter C.; Schramm, Vern L.

In: Chemistry and Biology, Vol. 19, No. 6, 22.06.2012, p. 721-730.

Research output: Contribution to journalArticle

Hazleton, Keith Z. ; Ho, Meng Chiao ; Cassera, Maria B. ; Clinch, Keith ; Crump, Douglas R. ; Rosario, Irving ; Merino, Emilio F. ; Almo, Steven C. ; Tyler, Peter C. ; Schramm, Vern L. / Acyclic immucillin phosphonates : Second-generation inhibitors of plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase. In: Chemistry and Biology. 2012 ; Vol. 19, No. 6. pp. 721-730.
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