Acyclic Immucillin Phosphonates: Second-Generation Inhibitors of Plasmodium falciparum Hypoxanthine- Guanine-Xanthine Phosphoribosyltransferase
| Autor: | Keith Clinch, Vern L. Schramm, Douglas R. Crump, Meng-Chiao Ho, Emilio F. Merino, Peter C. Tyler, Keith Z. Hazleton, Maria B. Cassera, Steve C. Almo, Irving Rosario |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Purine
Models Molecular Erythrocytes Plasmodium falciparum Clinical Biochemistry Molecular Conformation Organophosphonates Purine nucleoside phosphorylase Biology Crystallography X-Ray 01 natural sciences Biochemistry Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Catalytic Domain parasitic diseases Drug Discovery medicine Hypoxanthine salvage Humans Nucleotide Prodrugs Pentosyltransferases Enzyme Inhibitors Inosine Molecular Biology Hypoxanthine 030304 developmental biology Cell Proliferation chemistry.chemical_classification Pharmacology 0303 health sciences Dose-Response Relationship Drug 010405 organic chemistry General Medicine 3. Good health 0104 chemical sciences chemistry Hypoxanthine-guanine phosphoribosyltransferase biology.protein Phosphoribosyltransferase Molecular Medicine medicine.drug |
| Zdroj: | Chemistry & Biology. 19(6):721-730 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2012.04.012 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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