Phosphonylmethyl ethers of acyclic nucleoside analogues: inhibitors of HSV-1 induced ribonucleotide reductase.
Diphosphates of N-(S)-(3-hydroxy-2-phosphonylmethoxypropyl) and N-(2-phosphonylmethoxyethyl) derivatives of purine and pyrimidine heterocyclic bases inhibit HSV-1 encoded ribonucleotide reductase. Of the compounds studied, the most efficient inhibitors of CDP reduction (at 5.1 mumols.l-1) by the HSV-1-encoded enzyme are HPMPApp (IC50 = 0.9 mumols.l-1) and PMEApp (IC50 = 8 mumol.l-1). PMEApp does not inhibit the enzyme isolated from the mutant HSV-1 KOS strain PMEAr which is resistant to PMEA at a concentration of 100 micrograms/ml. The enzyme isolated from the PMEA-resistant virus strain is also insensitive to inhibitory effects of hydroxyurea and HPMPApp. Thus, the inhibitory potency of HPMPApp and PMEApp toward HSV-1 encoded ribonucleotide reductase might be connected with the anti-HSV activity of HPMPA and PMEA.
Cerný
J
J
Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, Prague.
Votruba
I
I
Vonka
V
V
Rosenberg
I
I
Otmar
M
M
Holý
A
A
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000187:drug effects*
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C053001:adefovir; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D012264:Ribonucleotide Reductases; D000225:Adenine