Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds: structure-activity relationships and antiherpetic activity in vivo.
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.
Manikowski
Andrzej
A
GLSynthesis Inc., One Innovation Drive, Worcester, Massachusetts 01605, USA.
Verri
Annalisa
A
Lossani
Andrea
A
Gebhardt
Bryan M
BM
Gambino
Joseph
J
Focher
Federico
F
Spadari
Silvio
S
Wright
George E
GE
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D003001:Cloning, Molecular; D020803:Encephalitis, Herpes Simplex / Q000188:drug therapy / Q000821:virology; D015828:Eye Infections, Viral / Q000188:drug therapy / Q000821:virology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology*; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D010766:Phosphorylation; D011688:Purinones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000302:isolation & purification; D014775:Virus Activation / Q000187:drug effects
C501705:2-phenylamino-9-(4-(1-decahydroquinolyl)butyl)-6-oxopurine; C091724:9-(4-hydroxybutyl)-N(2)-phenylguanine; D000998:Antiviral Agents; D011688:Purinones; D011994:Recombinant Proteins; D006147:Guanine; D013937:Thymidine Kinase