Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds: structure-activity relationships and antiherpetic activity in vivo
GLSynthesis Inc.; Department of Biochemistry and Molecular Pharmacology
Animals; Antiviral Agents; Cloning, Molecular; Encephalitis, Herpes Simplex; Eye Infections, Viral; Guanine; Herpesvirus 1, Human; Herpesvirus 2, Human; Mice; Phosphorylation; Purinones; Recombinant Proteins; purification; Structure-Activity Relationship; Thymidine Kinase; purification; Virus Activation
Life Sciences | Medicine and Health Sciences
Derivatives of the herpes simplex thymidine kinase inhibitor HBPG [2-phenylamino-9-(4-hydroxybutyl)-6-oxopurine] have been synthesized and tested for inhibitory activity against recombinant enzymes (TK) from herpes simplex types 1 and 2 (HSV-1, HSV-2). The compounds inhibited phosphorylation of [3H]thymidine by both enzymes, but potencies differed quantitatively from those of HBPG and were generally greater for HSV-2 than HSV-1 TKs. Changes in inhibitory potency were generally consistent with the inhibitor/substrate binding site structure based on published X-ray structures of HSV-1 TK. In particular, several 9-(4-aminobutyl) analogues with bulky tertiary amino substituents were among the most potent inhibitors. Variable substrate assays showed that the most potent compound, 2-phenylamino-9-[4-(1-decahydroquinolyl)butyl]-6-oxopurine, was a competitive inhibitor, with Ki values of 0.03 and 0.005 microM against HSV-1 and HSV-2 TKs, respectively. The parent compound HBPG was uniquely active in viral infection models in mice, both against ocular HSV-2 reactivation and against HSV-1 and HSV-2 encephalitis. In assays lacking [3H]thymidine, HBPG was found to be an efficient substrate for the enzymes. The ability of the TKs to phosphorylate HBPG may relate to its antiherpetic activity in vivo.
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Citation: J Med Chem. 2005 Jun 2;48(11):3919-29. Link to article on publisher's site
DOI of Published Version
Journal of medicinal chemistry
Manikowski, Andrzej; Verri, Annalisa; Lossani, Andrea; Gebhardt, Bryan M.; Gambino, Joseph J.; Focher, Federico; Spadari, Silvio; and Wright, George E., "Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds: structure-activity relationships and antiherpetic activity in vivo" (2005). Open Access Articles. 1154.