Amenamevir, a Helicase-Primase Inhibitor, for the Optimal Treatment of Herpes Zoster

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.

Herpes zoster: A Review of Clinical Manifestations and Management

“…Helicase-primase inhibitors (HPIs) such as amenamevir inhibit the progression of the replication fork, an initial step in DNA synthesis to separate the double strand into two single strands. Amenamevir is the first compound of this new class and has received approval for HZ treatment in Japan [93].…”

40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs?

“…The next compounds were synthetized at the beginning of the 21th century. It seems that HPIs are highly effective against skin and vaginal herpes infection in vitro and in vivo, have low cytotoxicity in vitro, and are well-tolerated in mice and humans [ 12 , 13 , 123 , 124 ]. Unlike ACV and its derivatives, HPIs do not require phosphorylation to the active form by viral kinase and show activity in uninfected cells [ 11 , 122 , 125 ].…”

“…Hitherto, three classes of herpesvirus HPIs were developed: 2-amino-thiazolylphenyl derivatives (BILS 179 BS), thiazole urea (BAY 57-1293; pritelivir), and oxadiazolylphenyl type (ASP2151, amenamevir) [ 12 ]. …”

“…It inhibits DNA-stimulated ATP hydrolysis and inhibits HSV helicase-primase activity by preventing DNA release during translocation. In the plaque formation assay (PFA), it has been shown that BILS 179 BS decreases HSV DNA replication of wild type HSV strains or ACV-resistant mutants cultured in cell culture [ 12 ]. The EC 50 of BILS 179 BS for HSV-1 and HSV-2 is 0.08–0.10 µM and 0.010–0.011 µM, respectively.…”

“…The viral protein UL30 with the function of DNA polymerase and the UL42 are responsible for the DNA synthesis. Virus thymidine kinase (UL23), ribonucleotide reductase (UL39/UL40), and deoxyuridine triphosphatase (UL50) are involved in the synthesis of deoxyribonucleotides triphosphate (dNTPs) [ 1 , 12 , 13 , 14 ].…”