Antiherpesvirus Activities of (1′
            <i>S</i>
            ,2′
            <i>R</i>
            )-9-{[1′,2′-Bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine (A-5021) in Cell Culture

Ono, Nobukazu; Ohmura, Yuko; Suzuki, Katsuya; Aoki, Miho; Nakazawa, Harumi; Oikawa, Miki; Kato, Tamamo; Okunishi, Masahiko; Nishiyama, Yukihiro; Yamanishi, Koichi

doi:10.1128/aac.42.7.1666

Cited by 34 publications

(15 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with prior reports of relatively low efficacy of ACV against VZV vis a vis HSV-1 infection (Iwayama et al, 1998), the test compounds showed a higher potency than ACV against VZV, at concentrations that produced relatively low cellular toxicity. In addition, HCMV infection was inhibited effectively.…”

Section: Discussionsupporting

confidence: 87%

Broad-spectrum non-nucleoside inhibitors of human herpesviruses

et al. 2015

View full text Add to dashboard Cite

Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of ‘quiescent’ HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo.

show abstract

Section: Discussionsupporting

confidence: 87%

Broad-spectrum non-nucleoside inhibitors of human herpesviruses

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Stocks of HSV (KOS), HSV-2 (UW-268), and VZV (Kawaguchi) were prepared as described previously (14).…”

Section: Methodsmentioning

confidence: 99%

“…A-5021, or (1ЈS,2ЈR)-9-{[1Ј,2Ј-bis(hydroxymethyl)cycloprop-1Ј-yl]methyl}guanine, is a novel guanosine analog with potent antiviral activity against herpes simplex virus type 1 (HSV-1), HSV-2, varicella-zoster virus (VZV), and human cytomegalovirus (14,23). The in vitro antiviral activity of A-5021 is higher than that of acyclovir (ACV) or penciclovir (PCV) against HSV-1, HSV-2, and VZV (14).…”

mentioning

confidence: 99%

“…The monophosphates of antiviral nucleosides are subsequently phosphorylated to triphosphates by cellular kinases (20,21). These triphosphates accumulate in virus-infected cells and inhibit viral DNA polymerases in a competitive and chain-terminated fashion (7,9,10,14,18). Some nucleoside analogs like PCV have prolonged antiviral activities derived from the long intracellular half-lives of their triphosphates (2,3,7,25).…”

mentioning

confidence: 99%

“…Some nucleoside analogs like PCV have prolonged antiviral activities derived from the long intracellular half-lives of their triphosphates (2,3,7,25). A-5021 also shows a prolonged in vitro antiviral effect (14).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Ono

Suzuki

Sekiyama

et al. 1998

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Strategies in the Design of Antiviral Drugs

Clercq

Herdewijn

2010

Pharmaceutical Sciences Encyclopedia

View full text Add to dashboard Cite

Effective vaccines have led to the eradication of important viral pathogens such as smallpox, polio, measles, mumps, and rubella. The strategies for interfering with the key events in the viral replicative cycle have the potential to target virtually all important human viral pathogens. This article focuses on approaches targeted at specific processes in viral infection, including virus adsorption, virus‐cell fusion, viral DNA or RNA synthesis, and viral enzymes.

show abstract

Antiherpesvirus Activities of (1′ S ,2′ R )-9-{[1′,2′-Bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine (A-5021) in Cell Culture

Cited by 34 publications

References 19 publications

Broad-spectrum non-nucleoside inhibitors of human herpesviruses

Broad-spectrum non-nucleoside inhibitors of human herpesviruses

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

Strategies in the Design of Antiviral Drugs

Contact Info

Product

Resources

About