Title

Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds: structure-activity relationships and antiherpetic activity in vivo

UMMS Affiliation

GLSynthesis Inc.; Department of Biochemistry and Molecular Pharmacology

Date

5-27-2005

Document Type

Article

Subjects

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

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: J Med Chem. 2005 Jun 2;48(11):3919-29. Link to article on publisher's site

DOI of Published Version

10.1021/jm049059x

Related Resources

Link to Article in PubMed

Journal Title

Journal of medicinal chemistry

PubMed ID

15916444