1. Academic Validation
  2. Helicase primase inhibitors (HPIs) are efficacious for therapy of human herpes simplex virus (HSV) disease in an infection mouse model

Helicase primase inhibitors (HPIs) are efficacious for therapy of human herpes simplex virus (HSV) disease in an infection mouse model

  • Antiviral Res. 2021 Nov:195:105190. doi: 10.1016/j.antiviral.2021.105190.
Nadja Uhlig 1 Anne-Kathrin Donner 1 Christian Gege 2 Franziska Lange 3 Gerald Kleymann 4 Thomas Grunwald 5
Affiliations

Affiliations

  • 1 Fraunhofer-Institute for Cell Therapy and Immunology IZI, Division Vaccines and Infection Models, Unit Preclinical Validation, Perlickstrasse 1, 04103, Leipzig, Germany.
  • 2 Innovative Molecules GmbH, Leopoldshöher Str. 7, 32107, Bad Salzuflen, Germany.
  • 3 Fraunhofer-Institute for Cell Therapy and Immunology IZI, Center for Experimental Medicine, Perlickstrasse 1, 04103, Leipzig, Germany.
  • 4 Innovative Molecules GmbH, Leopoldshöher Str. 7, 32107, Bad Salzuflen, Germany; University of Tübingen, Interfaculty Institute of Biochemistry, Auf der Morgenstelle 34, 72076, Tübingen, Germany.
  • 5 Fraunhofer-Institute for Cell Therapy and Immunology IZI, Division Vaccines and Infection Models, Unit Preclinical Validation, Perlickstrasse 1, 04103, Leipzig, Germany. Electronic address: thomas.grunwald@izi.fraunhofer.de.
Abstract

Although the seroprevalence of Herpes simplex virus type 1 (HSV-1) currently amounts to ∼ 67% worldwide, the annual incidence of a severe disease progression, particularly herpes encephalitis, is approximately 2-4 cases per 1,000,000 infections. Nucleoside analogues, such as acyclovir (ACV), valacyclovir (VACV) or famciclovir, are still the therapeutic treatment of choice for HSV infections. However, nucleoside drugs have limited efficacy against severe HSV disease and for treatment of nucleoside-resistant viral strains, alternative therapies such as helicase-primase inhibitors (HPIs) which are highly potent by inhibiting viral replication are under development. In preclinical studies we analyzed the Antiviral efficacy of drug candidates of a novel compound class of HPIs for the treatment of HSV to identify the most active eutomer structure in an intranasal Infection mouse lethal challenge model. HSV-1 infected BALB/c mice treated with vehicle control developed fatal disease according to humane endpoints after 5-7 days. In contrast, the Animals dosed orally once daily with the HPI compounds at 10 or 4 mg/kg/day showed a significantly increased survival (70% and 100% for 10 mg/kg/day; 90% and 100% for 4 mg/kg/day, respectively) compared to the vehicle treatment (0-10%), when therapy was initiated 6 h post HSV-1 inoculation. We observed a significantly improved outcome in clinical parameters and survival over 21 days in the group receiving novel HPI candidates using even the lowest dose of 4 mg/kg/day. With VACV treatment of 75 mg/kg daily survival was also significantly increased (80%-90% for 75 mg/kg/day) but to lesser extent. Initial IM-250 therapy at 10 mg/kg/day could be delayed up to 72 h resulting in significantly increased survival compared to the vehicle control. Furthermore, we detected significantly fewer viral genome copies in the lungs and brains of HPI treated Animals compared to vehicle (440-fold reduction for 4 mg/kg/day IM-250 in the brain) or VACV controls by quantitative PCR. In conclusion the preclinical studies of the novel HPI compounds showed superior efficacy in comparison to the current standard HSV treatment represented by VACV with respect to the survival according humane endpoints, the clinical score and virus load in lungs and brains. Thus, candidates of this new drug class are promising antivirals of HSV infections and further translation into clinical trials is warranted.

Keywords

Antiviral therapy; Helicase-primase inhibitor; Herpes simplex virus; IM-250; Mouse lethal challenge model.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-150306
    99.94%, 解旋酶引物酶抑制剂
    HSV