Mode of action of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl) cycloprop-1'-yl]methyl]guanine (A-5021) against herpes simplex virus type 1 and type 2 and varicella-zoster virus.
The mode of action of (1'S,2'R)-9-([1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl)guanine (A-5021) against herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV) was studied. A-5021 was monophosphorylated at the 2' site by viral thymidine kinases (TKs). The 50% inhibitory values for thymidine phosphorylation of A-5021 by HSV-1 TK and HSV-2 TK were comparable to those for penciclovir (PCV) and lower than those for acyclovir (ACV). Of these three agents, A-5021 inhibited VZV TK most efficiently. A-5021 was phosphorylated to a mono-, di-, and triphosphate in MRC-5 cells infected with HSV-1, HSV-2, and VZV. A-5021 triphosphate accumulated more than ACV triphosphate but less than PCV triphosphate in MRC-5 cells infected with HSV-1 or VZV, whereas HSV-2-infected MRC-5 cells had comparable levels of A-5021 and ACV triphosphates. The intracellular half-life of A-5021 triphosphate was considerably longer than that of ACV triphosphate and shorter than that of PCV triphosphate. A-5021 triphosphate competitively inhibited HSV DNA polymerases with respect to dGTP. Inhibition was strongest with ACV triphosphate, followed by A-5021 triphosphate and then (R,S)-PCV triphosphate. A DNA chain elongation experiment revealed that A-5021 triphosphate was incorporated into DNA instead of dGTP and terminated elongation, although limited chain extension was observed. Thus, the strong antiviral activity of A-5021 appears to depend on a more rapid and stable accumulation of its triphosphate in infected cells than that of ACV and on stronger inhibition of viral DNA polymerase by its triphosphate than that of PCV.
Ono
N
N
Life Science Laboratories, Ajinomoto Co., Inc., Totsuka-ku, Yokohama 244, Japan.
Iwayama
S
S
Suzuki
K
K
Sekiyama
T
T
Nakazawa
H
H
Tsuji
T
T
Okunishi
M
M
Daikoku
T
T
Nishiyama
Y
Y
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors; D010766:Phosphorylation; D013936:Thymidine / Q000378:metabolism
C111645:9-((cis-1,2-bis(hydroxymethyl)cycloprop-1-yl)methyl)guanine; D000998:Antiviral Agents; D004279:DNA, Viral; D019384:Nucleic Acid Synthesis Inhibitors; D006147:Guanine; D013936:Thymidine