Antiviral potential of combinations of etiotropic antiherpetic agents including LAS-131, a novel terminase complex inhibitor, to affect the reproduction of herpes simplex virus type 1 (Orthoherpesviridae: Simplexvirus: Simplexvirus humanalpha1)

Introduction. Herpes simplex virus type 1 (HSV-1) causes various diseases in humans that can lead to disability and death. Current treatments are effective and relatively safe. However, the high prevalence of HSV, the necessity for long-term therapy associated with the development of drug resistance in the virus (mainly in immunocompromised patients) and severe side effects of second-line drugs complicate treatment. Obviously, there is a necessity to develop therapeutic agents with a new mechanism of action and new ways of influencing herpes infection to improve the effectiveness of therapy. The combined use of drugs with different mechanisms of action is one such approach. The aim of the study is to evaluate the antiviral activity of combinations of LAS-131 ((3S)-4-[6-(purin-6-yl)aminohexanoyl]-3,4-dihydro-3-methyl-7,8-difluoro-2H-[1,4]-benzoxazine) with basic antiherpetic drugs and with two new compounds. Materials and methods. The effect of LAS-131 combinations against HSV-1 was studied by constructing an isobologram and calculating the fractional inhibitory concentration index. Results. LAS-131 selectively inhibits the reproduction of acyclovir-sensitive and -resistant HSV-1 variants (IC50 is 1.95 μg/mL, selectivity index is 63). Its target protein is the large subunit of the terminase complex (pUL15). When LAS-131 is used in combination with viral DNA polymerase inhibitors (acyclovir and related compounds) or with the minor-groove inhibitor 15Lys-bis-netropsin, a potentiating effect is observed, which allows decreasing the concentrations of the combined compounds by 4 times or more while maintaining antiviral activity. LAS-131 interacted additively with foscarnet, ribavirin, and α-interferon. Conclusion. Combinations of LAS-131 with known antiviral agents have been established, providing synergistic and additive effects of interaction against HSV-1.