Abstract
Acyclovir, valacyclovir, and famciclovir are used for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Helicase-primase inhibitors (HPIs) inhibit replication fork progression that separates double DNA strands into two single strands during DNA synthesis. The HPIs amenamevir and pritelivir have novel mechanisms of anti-herpetic action, and their once-daily administration has clinical efficacy for genital herpes. Among HPIs, amenamevir has anti-VZV activity. The concentrations of HSV-1 and VZV required for the 50% plaque reduction of amenamevir were 0.036 and 0.047 μM, respectively. We characterized the features of amenamevir regarding its mechanism, resistance, and synergism with acyclovir. Its antiviral activity was not influenced by the viral replication cycle, in contrast to acyclovir. A clinical trial of amenamevir for herpes zoster demonstrated its non-inferiority to valacyclovir. To date, amenamevir has been successfully used in over 1,240,000 patients with herpes zoster in Japan. Post-marketing surveillance of amenamevir in Japan reported side effects with significant potential risk identified by the Japanese Risk Management Plan, including thrombocytopenia, gingival bleeding, and palpitations, although none of these were serious. The clinical efficacy and safety profiles of amenamevir were established in patients with herpes zoster. Therefore, amenamevir as an HPI opens a new era of anti-herpes therapy.
Highlights
Varicella-zoster virus (VZV) infection, which causes varicella and herpes zoster, is treated with antivirals
Helicase-primase inhibitors (HPIs) have been developed as new anti-herpes drugs, but currently only amenamevir among the HPIs is used for the treatment of herpes zoster
Amenamevir has a low EC50 to herpes simplex virus (HSV) and VZV and its efficacy in HSV-infected animals and synergism with acyclovir and penciclovir was indicated for the combinational treatment of severe infection with
Summary
Varicella-zoster virus (VZV) infection, which causes varicella and herpes zoster, is treated with antivirals. DNA at the replication fork, separating double-stranded DNA into two single strands, and synthesizing RNA primers followed by Okazaki fragments in the lagging strand for DNA synthesis. HSV UL52 and VZVORF55 (primase) synthesize RNA primers HSV UL52 and VZVORF55 (primase) synthesize RNA primers (followed by Okazaki by Okazaki fragments) for lagging strand DNA synthesis. The to single-stranded binding protein destabilizing activity, arrows indicate the direction of movement of the DNA replication proteins. (UL29 of HSV and VZV), binds to a single-stranded template DNA with helix destabilizing activity. Amenamevir has anti-HSV and anti-VZV activity, while, in contrast, pritelivir and BILS 22. We focus on the anti-HSV and anti-VZV activities of amenamevir and discuss the differences in its antiviral activity compared with acyclovir
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