BIOMAT Database Logo BIOMAT Database Logo

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. 1998

N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
Life Science Laboratories, Ajinomoto Co., Inc., Totsuka-ku, Yokohama 244, Japan.

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.

UI MeSH Term Description Entries
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004279 DNA, Viral Deoxyribonucleic acid that makes up the genetic material of viruses. Viral DNA
D006147 Guanine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D013936 Thymidine A nucleoside in which THYMINE is linked to DEOXYRIBOSE. 2'-Deoxythymidine,Deoxythymidine,2' Deoxythymidine
D014645 Herpesvirus 3, Human The type species of VARICELLOVIRUS causing CHICKENPOX (varicella) and HERPES ZOSTER (shingles) in humans. Chickenpox Virus,Herpes zoster Virus,Ocular Herpes zoster Virus,VZ Virus,Varicella-Zoster Virus,HHV-3,Herpesvirus 3 (alpha), Human,Herpesvirus Varicellae,Human Herpesvirus 3,Chickenpox Viruses,Herpes zoster Viruses,VZ Viruses,Varicella Zoster Virus,Varicella-Zoster Viruses,Varicellae, Herpesvirus
D018258 Herpesvirus 2, Human A species of SIMPLEXVIRUS associated with genital infections (HERPES GENITALIS). It is transmitted by sexual intercourse and close personal contact. HSV-2,Herpes Simplex Virus 2,Human Herpesvirus 2,HHV-2,Herpes Simplex Virus Type 2,Herpesvirus 2 (alpha), Human
D018259 Herpesvirus 1, Human The type species of SIMPLEXVIRUS causing most forms of non-genital herpes simplex in humans. Primary infection occurs mainly in infants and young children and then the virus becomes latent in the dorsal root ganglion. It then is periodically reactivated throughout life causing mostly benign conditions. HSV-1,Herpes Simplex Virus 1,HHV-1,Herpes Simplex Virus Type 1,Herpesvirus 1 (alpha), Human,Human Herpesvirus 1

Related Publications

N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
Anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)-cycloprop-1'-yl]methyl] x guanine (A-5021) in vitro and in vivo.
February 2001, Antiviral research,
N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
Evaluation of the antiviral activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (A-5021) against equine herpesvirus type 1 in cell monolayers and equine nasal mucosal explants.
February 2012, Antiviral research,
N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
Synthesis and biological activity of tricyclic analogues of 9-[[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine.
May 2006, Bioorganic & medicinal chemistry,
N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
The anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)-cycloprop-1'-yl]methyl]guanine is markedly potentiated by the immunosuppressive agent mycophenolate mofetil.
February 2001, Antiviral research,
N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
Efficacy of BW759 (9-[[2-hydroxy-1(hydroxymethyl)ethoxy]methyl]guanine) against herpes simplex virus type 1 keratitis in rabbits.
August 1984, Current eye research,
N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
Synthesis and anti-VZV activity of 6-heteroaryl derivatives of tricyclic acyclovir and 9-{[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl}guanine analogues.
August 2009, European journal of medicinal chemistry,
N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
Mode of action of (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine against herpesviruses.
August 1995, Antimicrobial agents and chemotherapy,
N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
A new nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxyl]methyl]guanine, highly active in vitro against herpes simplex virus types 1 and 2.
July 1982, Antimicrobial agents and chemotherapy,
N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
Unique spectrum of activity of 9-[(1,3-dihydroxy-2-propoxy)methyl]-guanine against herpesviruses in vitro and its mode of action against herpes simplex virus type 1.
May 1983, Proceedings of the National Academy of Sciences of the United States of America,
N Ono, and S Iwayama, and K Suzuki, and T Sekiyama, and H Nakazawa, and T Tsuji, and M Okunishi, and T Daikoku, and Y Nishiyama
Pharmacokinetics and antiviral activity in simian varicella virus-infected monkeys of (R,S)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine, an anti-varicella-zoster virus drug.
December 1988, Antimicrobial agents and chemotherapy,
Copied contents to your clipboard!