Sensitivity of monkey B virus (Cercopithecine herpesvirus 1) to antiviral drugs: role of thymidine kinase in antiviral activities of substrate analogs and acyclonucleosides.
Herpes B virus (B virus [BV]) is a macaque herpesvirus that is occasionally transmitted to humans where it can cause rapidly ascending encephalitis that is often fatal. To understand the low susceptibility of BV to the acyclonucleosides, we have cloned, expressed, and characterized the BV thymidine kinase (TK), an enzyme that is expected to "activate" nucleoside analogs. This enzyme is similar in sequence and properties to the TK of herpes simplex virus (HSV), i.e., it has a broad substrate range and low enantioselectivity and is sensitive to inhibitors of HSV TKs. The BV enzyme phosphorylates some modified nucleosides and acyclonucleosides and l enantiomers of thymidine and related antiherpetic analogs. However, the potent anti-HSV drugs acyclovir (ACV), ganciclovir (GCV), and 5-bromovinyldeoxyuridine were poorly or not phosphorylated by the BV enzyme under the experimental conditions. The antiviral activities of a number of marketed antiherpes drugs and experimental compounds were compared against BV strains and, for comparison, HSV type 1 (HSV-1) in Vero cell cultures. For most compounds tested, BV was found to be about as sensitive as HSV-1 was. However, BV was less sensitive to ACV and GCV than HSV-1 was. The abilities of thymidine analogs and acyclonucleosides to inhibit replication of BV in Vero cell culture were not always proportional to their substrate properties for BV TK. Our studies characterize BV TK for the first time and suggest new lead compounds, e.g., 5-ethyldeoxyuridine and pencyclovir, which may be superior to ACV or GCV as treatment for this emerging infectious disease.
Focher
Federico
F
GLSynthesis Inc., One Innovation Drive, Worcester, MA 01605, USA.
Lossani
Andrea
A
Verri
Annalisa
A
Spadari
Silvio
S
Maioli
Andrew
A
Gambino
Joseph J
JJ
Wright
George E
GE
Eberle
Richard
R
Black
Darla H
DH
Medveczky
Peter
P
Medveczky
Maria
M
Shugar
David
D
D000212:Acyclovir / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006147:Guanine; D006568:Herpesvirus 1, Cercopithecine / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008826:Microbial Sensitivity Tests / Q000379:methods; D008969:Molecular Sequence Data; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D013379:Substrate Specificity; D013936:Thymidine / Q000031:analogs & derivatives / Q000378:metabolism; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; C022811:edoxudin; C053539:penciclovir; D006147:Guanine; D013937:Thymidine Kinase; D013936:Thymidine; D003857:Deoxyuridine; D000212:Acyclovir