Susceptibility of clinical isolates, laboratory-adapted and drug-resistant herpes simplex virus strains to helicase-primase inhibitor adibelivir (IM-250) and its synergy in combination therapy with acyclovir, penciclovir and foscarnet

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Herpes simplex virus (HSV) infections are widespread and cause a significant global health burden. Clinical manifestations range from herpes labialis and genital herpes to life-threatening herpes simplex encephalitis or neonatal herpes. Current treatment relies on nucleoside analogs such as acyclovir, valacyclovir or famciclovir. The emergence of resistance to these drugs is of concern in transplant recipients and immunocompromised patients. Next-generation helicase-primase inhibitors are under clinical development to provide more efficacious treatments and addressi resistance to current therapies. Adibelivir (IM-250) is a potent HSV helicase-primase inhibitor (HPI) with nanomolar activity against both HSV1 and HSV2. In the present study, we assessed the susceptibility of more than 50 clinical isolates and laboratory strains against adibelivir. Across all strains tested, Adibelivir inhibited HSV replication in cell culture with mean EC 50 values of 21 nM (HSV1) and 35 nM (HSV2), compared to up to 42-fold higher EC 50 values for acyclovir (883 nM for HSV1 and 1456 nM for HSV2). No preexisting variants with a lack of susceptibility were identified. Furthermore, no cross-resistance was observed between nucleoside analogs and HPIs and finally, the antiviral activity depended on serum concentration and infectious dose. Collectively, these data establish the baseline susceptibility profile of HSV clinical isolates to adibelivir prior to its broader clinical introduction. Adibelivir retains activity against nucleoside-resistant HSV strains and exhibits synergistic antiviral effects when combined with acyclovir, penciclovir and foscarnet in vitro . These results support clinical evaluation of adibelivir as a therapeutic option for HSV infections and as a candidate for combination therapy.

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