viruses Review Amenamevir, a Helicase-Primase Inhibitor, for the Optimal Treatment of Herpes Zoster Kimiyasu Shiraki 1,*, Shinichiro Yasumoto 2, Nozomu Toyama 3 and Hiroaki Fukuda 4 1 Faculty of Nursing, Senri Kinran University, 5-25-1 Fujishirodai, Suita, Osaka 565-0873, Japan 2 Yasumoto Dermatology Clinic, Tsukushino, Fukuoka 818-0083, Japan; [email protected] 3 Toyama Dermatologic Clinic, Aburatsu, Nichinan City, Miyazaki 887-0001, Japan; [email protected] 4 Maruho Co., Ltd., Nakatsu, Osaka 531-0071, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-6-6872-7139 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 Citation: Shiraki, K.; Yasumoto, S.; none of these were serious. The clinical efficacy and safety profiles of amenamevir were established Toyama, N.; Fukuda, H. Amenamevir, a Helicase-Primase Inhibitor, for the in patients with herpes zoster. Therefore, amenamevir as an HPI opens a new era of anti-herpes Optimal Treatment of Herpes Zoster. therapy. Viruses 2021, 13, 1547. https:// doi.org/10.3390/v13081547 Keywords: amenamevir; helicase-primase inhibitor; herpes simplex virus; varicella-zoster virus; herpes zoster; antivirals Academic Editor: Barry J. Margulies Received: 30 June 2021 Accepted: 3 August 2021 1. Introduction Published: 5 August 2021 Varicella-zoster virus (VZV) infection, which causes varicella and herpes zoster, is treated with antivirals. Elion developed acyclovir for systemic administration to treat Publisher’s Note: MDPI stays neutral herpes simplex virus (HSV) and VZV infections [1–3]. Penciclovir, valacyclovir, and with regard to jurisdictional claims in famciclovir are currently used for preventing and treating HSV and VZV infections [4]. published maps and institutional affil- The antiherpetic drugs valacyclovir (acyclovir) and famciclovir (penciclovir) have iations. been developed for the treatment and prevention of apparent HSV and VZV infections. New antiherpetic drugs with different mechanisms of action have been developed as novel helicase-primase (HP) inhibitors (HPIs) of HSV and VZV. Double-stranded DNA is sepa- rated into two single strands (replication fork) before DNA synthesis, and complementary Copyright: © 2021 by the authors. strands are synthesized from each DNA strand to produce two new double-stranded DNA Licensee MDPI, Basel, Switzerland. molecules during DNA replication, as shown in Figure1. The HP complex unwinds viral This article is an open access article DNA at the replication fork, separating double-stranded DNA into two single strands, and distributed under the terms and synthesizing RNA primers followed by Okazaki fragments in the lagging strand for DNA conditions of the Creative Commons synthesis. Then, DNA polymerase initiates complementary DNA synthesis in the two Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ separated DNA strands. The HP complex consists of three proteins: HSV UL5/VZVORF55 4.0/). (helicase), HSV UL52/VZVORF6 (primase), and HSV UL8/VZVORF52 (cofactor). Viruses 2021, 13, 1547. https://doi.org/10.3390/v13081547 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 21 Viruses 2021, 13, 1547 HSV UL5/VZVORF55 (helicase), HSV UL52/VZVORF6 (primase), and HSV 2 of 21 UL8/VZVORF52 (cofactor). Figure 1. The viral helicase primase (HP) complex in viral DNA synthesis (modified from [5]). The figure shows the role of Figure 1. The viral helicase primase (HP) complex in viral DNA synthesis (modified from [5]). The figure shows the role the HPof the complex HP complex (UL5, (UL5, UL8, UL8, and UL52and UL52 of HSV of HSV and and ORF55, ORF55, ORF6, ORF6, and and ORF52 ORF52 of of VZV), VZV), the the DNA DNA polymerasepolymerase complex complex (UL42 and UL30(UL42 ofand HSV UL30 and of ORF28HSV and of VZV:ORF28 DNA of VZV: polymerase), DNA polymerase) and the, ICP8and the single-stranded ICP8 single-stranded DNA bindingDNA binding protein protein of HSV of (ORF29 of VZV).HSV (ORF29 HSV UL5 of VZV). and VZVORF55HSV UL5 and (helicase) VZVORF55 relax (helicase) double-stranded relax double-strande DNA andd DNA separate and separate double double strands strands into into two single strands,two single forming strands, a replication forming a fork. replication HSV UL52 fork. HSV and VZVORF55UL52 and VZVORF55 (primase) (primase) synthesize synthesize RNA primers RNA primers (followed (followed by Okazaki by Okazaki fragments) for lagging strand DNA synthesis. DNA polymerase contains intrinsic ribonuclease H (RNase H) fragments)activity forthat lagging specifically strand degrades DNA RNA/DNA synthesis. heteroduplexes DNA polymerase formed contains from RNA intrinsic primer ribonuclease-Okazaki fragment H (RNases and the H) activitytem- that specificallyplate DNA degrades complex. RNA/DNA DNA polymerase heteroduplexes and its accessory formed protein from (UL42) RNA primer-Okazakibind to each single fragments strand and andsynthesize the template com- DNA complex.plementary DNA DNA polymerase to each strand and itsof the accessory replication protein fork. The (UL42) single bind-stranded to each DNA single binding strand protein and with synthesize helix destabilizing complementary DNAactivit to eachy, ICP8 strand (UL29 ofthe of HSV replication and VZV), fork. binds The to single-stranded a single-stranded DNA template binding DNA protein with withhelix helixdestabilizing destabilizing activity activity,. The ICP8 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. The arrows indicate the direction of movement of the DNAAreplication 2-amino thiazole proteins. compound, T157602, was reported as an HSV-2 HPI [6] and there- after two HPIs, BILS 22 BS and Bay 57-1293 (pritelivir), were shown to have anti-HSV activityA 2-amino in vitro and thiazole therapeutic compound, activity in T157602, murine HSV was models reported [7–9] as. Next, an HSV-2 three classes HPI [6] and thereafterof herpesvirus two HPIs, HPIs BILSwere 22 developed BS and Bay: thiazole 57-1293 urea (pritelivir), (pritelivir were [9]) shown, 2-amino to- havethiazol- anti-HSV activityylphenylin derivatives vitro and therapeutic(BILS 179 BS activity [8]), and in murineoxadiazolylphenyl HSV models type [7 –(9ASP2151]. Next,, threeame- classes ofnamevir herpesvirus) [10]. Amenamevir HPIs were developed: has anti-HSV thiazole and anti urea-VZV (pritelivir activity, while, [9]), 2-amino-thiazolylphenyl in contrast, prite- derivativeslivir and BILS (BILS 22 BS 179 have BS anti [8]),-HSV and activity oxadiazolylphenyl but lack anti-VZV type activity (ASP2151,. Clinical amenamevir) studies of [10]. AmenamevirHPIs on genital has herpes anti-HSV using andamenamevir anti-VZV and activity, pritelivir while, have in been contrast, conducted pritelivir [11–13] and. BILS 22 BS haveWe anti-HSVcharacterized activity the profile but lack of the anti-VZV anti-HSV activity.and anti- ClinicalVZV activities studies of amenamevir of HPIs on genital herpes[14–18] using. The antiviral amenamevir activity and of amenamevir pritelivir have was beennot influenced conducted by [viral11–13 DNA]. synthesis, althoughWe characterized that of acyclovir the was profile attenuated of the[17,18] anti-HSV. Amenamevir and anti-VZVwas licensed activities for the treat- of amena- ment of herpes zoster on the basis of a clinical trial on herpes zoster treatment in Septem- mevir [14–18]. The antiviral activity of amenamevir was not influenced by viral DNA ber 2017 [19]. In this review, we focus on the anti-HSV and anti-VZV activities of ame- synthesis, although that of acyclovir was attenuated [17,18]. Amenamevir was licensed for namevir and discuss the differences in its antiviral activity compared with acyclovir. the treatment of herpes zoster on the basis of a clinical trial on herpes zoster treatment in September 2017 [19]. In this review, we focus on the anti-HSV and anti-VZV activities of amenamevir and discuss the differences in its antiviral activity compared with acyclovir. 2. Role of HP in DNA Synthesis Double-stranded DNA needs to be separated into two single strands (replication fork) for DNA synthesis, and these two separated complementary strands proceed to form two new double-stranded DNA molecules during DNA