Characterization of virus strains resistant to the herpes virus helicase–primase inhibitor ASP2151 (Amenamevir)

Chono, Koji; Katsumata, Kiyomitsu; Kontani, Toru; Shiraki, Kimíyasu; Suzuki, Hiroshi

doi:10.1016/j.bcp.2012.05.020

Cited by 26 publications

(30 citation statements)

References 35 publications

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“…148 ASP2151 is also effective against thymidine kinase–deficient HSV strains resistant to acyclovir, 149 and resistance to ASP2151 is 1000 times less common than seen for acyclovir. 150 When administered to patients with genital herpes, ASP2151 significantly reduces the median time for lesion healing. 151,152 …”

Section: Proof Of Concept: Hsv Helicase/primase Inhibitorsmentioning

confidence: 99%

Discovering New Medicines Targeting Helicases: Challenges and Recent Progress

et al. 2013

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Helicases are ubiquitous motor proteins that separate and/or rearrange nucleic acid duplexes in reactions fueled by adenosine triphosphate (ATP) hydrolysis. Helicases encoded by bacteria, viruses, and human cells are widely studied targets for new antiviral, antibiotic, and anticancer drugs. This review summarizes the biochemistry of frequently targeted helicases. These proteins include viral enzymes from herpes simplex virus, papillomaviruses, polyomaviruses, coronaviruses, the hepatitis C virus, and various flaviviruses. Bacterial targets examined include DnaB-like and RecBCD-like helicases. The human DEAD-box protein DDX3 is the cellular antiviral target discussed, and cellular anticancer drug targets discussed are the human RecQ-like helicases and eIF4A. We also review assays used for helicase inhibitor discovery and the most promising and common helicase inhibitor chemotypes, such as nucleotide analogues, polyphenyls, metal ion chelators, flavones, polycyclic aromatic polymers, coumarins, and various DNA binding pharmacophores. Also discussed are common complications encountered while searching for potent helicase inhibitors and possible solutions for these problems.

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Section: Proof Of Concept: Hsv Helicase/primase Inhibitorsmentioning

confidence: 99%

Discovering New Medicines Targeting Helicases: Challenges and Recent Progress

et al. 2013

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“…A single mutation in UL52 (Ala899Thr, HSV-1) confers resistance to BAY 57-1293 (Figure 4B); however, this mutant remains sensitive to BILS 22 BS [121]. This again suggests that the BILS compounds may have different binding sites and/or mechanisms than BAY 57-1293.…”

Section: Hsv Helicase–primase As a Target For Antiviral Therapymentioning

confidence: 99%

“…One ASP2151 resistant mutant has been isolated and found to contain an Arg367His substitution [122]. This ASP2151-resistant mutant showed attenuated growth in tissue culture and reduced pathogenicity in vivo compared with the parent strain [121]. All of the resistance mutants were still susceptible to nucleoside analogue antiviral compounds.…”

Section: Hsv Helicase–primase As a Target For Antiviral Therapymentioning

confidence: 99%

“…Since both primase and helicase activity require movement along the DNA, this would provide a simple mechanism for simultaneously inhibiting both activities even though the catalytic cores for each activity reside on different subunits. On the other hand, UL52 mutants resistant to HPIs are relatively rare and have only been observed following growth of virus in the presence of BAY57-1293 and ASP2151 [120,121] and not with the BILS compounds. BAY57-1293 and ASP2151 may thus act by a different mechanism from the BILS compounds and/or their binding site may also include the primase subunit, UL52 [121,122].…”

Section: Hsv Helicase–primase As a Target For Antiviral Therapymentioning

confidence: 99%

“…On the other hand, UL52 mutants resistant to HPIs are relatively rare and have only been observed following growth of virus in the presence of BAY57-1293 and ASP2151 [120,121] and not with the BILS compounds. BAY57-1293 and ASP2151 may thus act by a different mechanism from the BILS compounds and/or their binding site may also include the primase subunit, UL52 [121,122]. Furthermore, mutants resistant to these two compounds map to different parts of the UL52 protein (Figure 4B), suggesting that they bind to different portions of the protein.…”

Section: Hsv Helicase–primase As a Target For Antiviral Therapymentioning

confidence: 99%

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The DNA helicase–primase complex as a target for herpes viral infection

Weller

Kuchta

2013

Expert Opinion on Therapeutic Targets

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Introduction The Herpesviridae are responsible for debilitating acute and chronic infections, and some members of this family are associated with human cancers. Conventional anti-herpesviral therapy targets the viral DNA polymerase and has been extremely successful; however, the emergence of drug-resistant virus strains, especially in neonates and immunocompromised patients, underscores the need for continued development of anti-herpes drugs. In this article, we explore an alternative target for antiviral therapy, the HSV helicase/primase complex. Areas covered This review addresses the current state of knowledge of HSV DNA replication and the important roles played by the herpesvirus helicase–primase complex. In the last 10 years several helicase/primase inhibitors (HPIs) have been described, and in this article, we discuss and contrast these new agents with established inhibitors. Expert opinion The outstanding safety profile of existing nucleoside analogues for a-herpesvirus infection make the development of new therapeutic agents a challenge. Currently used nucleoside analogues exhibit few side effects and have low occurrence of clinically relevant resistance. For HCMV, however, existing drugs have significant toxicity issues and the frequency of drug resistance is high, and no antiviral therapies are available for EBV and KSHV. The development of new anti-herpesvirus drugs is thus well worth pursuing especially for immunocompromised patients and those who develop drug-resistant infections. Although the HPIs are promising, limitations to their development into a successful drug strategy remain.

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Herpes Simplex Viruses

Birkmann

2021

New Drug Development for Known and Emerging Viruses

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Characterization of virus strains resistant to the herpes virus helicase–primase inhibitor ASP2151 (Amenamevir)

Cited by 26 publications

References 35 publications

Discovering New Medicines Targeting Helicases: Challenges and Recent Progress

Discovering New Medicines Targeting Helicases: Challenges and Recent Progress

The DNA helicase–primase complex as a target for herpes viral infection

Herpes Simplex Viruses

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