China
Africa
Explore chapters and articles related to this topic
Herpes Simplex Virus and Human CNS Infections
Published in Sunit K. Singh, Daniel Růžek, Neuroviral Infections, 2013
Marcela Kúdelová, Július Rajčáni
In 1997, a model for HSV DNA replication was formulated (Boehmer and Lehman 1997). Once the β proteins are expressed, a number of proteins localize into the nucleus and assemble in DNA replication complexes at prereplicative sites, where viral DNA synthesis initiates on the circular molecule. Then, the UL9 (the origin binding) protein binds to specific elements—origin of replication (either OriL or Oris)—thus beginning to unwind the DNA. Then, it recruits ICP8 (the ssDNA binding protein) to the unwound ssDNA and they both recruit the five other viral replication proteins (helicase–primase complex of three proteins UL5, UL8, and UL52, viral DNA polymerase catalytic subunit UL30, and its processivity factor UL42) to begin the initial round of θ (theta) form replication (Wu et al. 1988). Leading strand synthesis involves the unwinding of the DNA and synthesis of a primer by the HSV helicase–primase complex. Then, replication switches from θ form to rolling circle mode, producing long head-to-tail concatemers of viral DNA by an unknown mechanism (Jacob et al. 1979). Concatemers are cleaved into monomeric molecules during packaging.
Potential therapeutic targets for Mpox: the evidence to date
Published in Expert Opinion on Therapeutic Targets, 2023
Siddappa N Byrareddy, Kalicharan Sharma, Shrikesh Sachdev, Athreya S. Reddy, Arpan Acharya, Kaylee M. Klaustermeier, Christian L Lorson, Kamal Singh
In addition to DNA polymerase, there are several other enzymatic proteins which participate in poxvirus genome replication. These include helicase-primase, and topoisomerase enzymes. Both are essential for poxvirus genome replication [25]. For example, amenamevir, a helicase-primase inhibitor of variola zoster virus has been approved in Japan, and pritelivir, an inhibitor of herpesvirus helicase-primase is in phase 3 clinical trials. Since, the poxvirus helicase-primase complex is essential for viral replication, it is an important therapeutic antiviral target. Efforts have been made to develop viral topoisomerase inhibitors. For example, (+)-Rutamarin inhibits Epstein – Barr virus topoisomerase at low micromolar IC50 [136]. The reported structure of variola virus topoisomerase can also aid in the drug-discovery efforts against MPX [137].
Helicase-primase inhibitors from Medshine Discovery Inc. (WO2018/127207 and WO2020/007355) for the treatment of herpes simplex virus infections – structure proposal for Phaeno Therapeutics drug candidate HN0037
Published in Expert Opinion on Therapeutic Patents, 2022
Christian Gege, Gerald Kleymann
Amenamevir (Figure 1) is a helicase-primase inhibitor (HPI) with antiviral activity against HSV-1/2 and varicella-zoster virus, which has been approved in Japan for the treatment of shingles in 2017 [5,6], clinical Phase III studies have been executed in herpes simplex patients and Maruho Co., Ltd. announced in December 2021 that it has filed its anti-herpes virus drug Amenalief® for an additional indication and dosage (200 mg tablet) for the treatment of recurrent herpes simplex in Japan [7]. Structurally unrelated is pritelivir, which inhibits only the helicase-primase complex of HSV-1 and -2 with high specificity [3]. Its clinical development [8,9] was complicated by findings of potentially aromatic primary sulfonamide class-related side effects which can be attributed to the strong off-target activity of pritelivir toward carbonic anhydrase (CA) [10]. Pritelivir was granted breakthrough therapy designation by the FDA for the treatment of HSV infections in acyclovir-resistant immunocompromised patients and the Phase III clinical trial (NCT03073967) is expected to be completed in March 2024. A first case report demonstrated both symptomatic and virological control for the duration of its use [11]. By replacing the primary sulfonamide in pritelivir by a sulfoximine moiety as in IM-250 [12], the CA off-target activity could be circumvented. In addition, the reduced topological polar surface area (TPSA) by introducing the difluorophenyl moiety allowed a higher exposure in neuronal (i.e. brain [12]) tissue and reduced the latent virus load in animal models. In a mouse model, initial pritelivir and IM-250 therapy could be delayed up to 72 h resulting in significantly increased survival of mice compared to the vehicle control [13–15].
Emergence of varicella-zoster virus resistance to acyclovir: epidemiology, prevention, and treatment
Published in Expert Review of Anti-infective Therapy, 2021
Kimiyasu Shiraki, Masaya Takemoto, Tohru Daikoku
HPIs inhibit single-stranded, DNA-dependent ATPase, helicase, and primase activities by binding to the helicase-primase complex [28–31]. Three HPIs, pritelivir, BILS 179 BS, and amenamevir (ASP2151), have anti-HSV activity, and amenamevir alone has anti-VZV activity [9,29,32,33]. Amenamevir is more effective for treating HSV skin lesions than valacyclovir, and HPI-resistant HSV mutants are susceptible to acyclovir and have attenuated growth in vitro and less pathogenicity than the parent virus in HSV mutant-infected mice [31]. Mutations in either the helicase or primase of the HP complex against amenamevir might confer defects in viral replication and pathogenicity. Amenamevir showed better efficacy in treating HSV skin lesions in immunocompromised mice than valacyclovir [34]. Synergism of amenamevir was observed with acyclovir, penciclovir, and vidarabine in the treatment of HSV-2 and VZV. Isobologram analysis of amenamevir with acyclovir showed synergism at all concentrations, and amenamevir exhibited synergism with acyclovir at low concentrations for treating HSV-1, HSV-2, and VZV [7]. The oral administration of the combination of amenamevir and valacyclovir showed significant synergistic activity in treating HSV-infected mice and maximized antiherpetic therapy. Combination therapy may be a useful approach to treat herpes infections suspected to be caused by nucleoside analog drug-resistant virus variants and represents a more effective therapeutic option than monotherapy in treating herpes encephalitis or patients with immunosuppression. The antiherpetic activity of amenamevir was not affected by the replication cycle of VZV and HSV, whereas the late phase of infected cells was 10 times less susceptible to acyclovir than immediately after infection, possibly because of the nucleotides supplied by RR [35,36].