Combined effect of basic antiherpetic drugs with a new inhibitor of the terminase complex of herpes simplex virus type 1 in Vero cell culture

More than 90% of the world’s population are carriers of herpes simplex virus type 1 (HSV-1). The infection manifests itself in the formation of blisters and ulcers on the face or genitals, and can cause blindness, encephalitis, and generalized infection. All modern first- and second-line antiherpetic drugs selectively inhibit viral DNA-polymerase. The purine-benzoxazine conjugate LAS-131 [(S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine], which we described earlier, uses the large subunit of the HSV-1 terminase complex as a biotarget and selectively inhibits its reproduction in vitro. For the first time, we have obtained fundamentally new results on the combined effect of LAS-131 on human herpesvirus infection with practically significant antiviral compounds – nucleoside analogues (acyclovir [ACV], penciclovir [PCV], ganciclovir [GCV], brivudine [BVDU], iododeoxyuridine [IDU], adenine arabinoside [Ara-A], as well as a nucleoside phosphonate analogue (cidofovir [CDV]) and a pirophosphate analogue (foscarnet [FOS]). Using a inhibition assay of cytopathic effect (CPE) induced by a virus, it was shown that when combined with LAS-131, the concentrations of the compounds in combinations providing inhibition of HSV-1-induced CPE by 50%, decreased by 2 times (additive effect, FOS) or more (synergistic effect, ACV, PCV, GCV, IDU, BVDU, Ara-A, CDV). Reducing the concentrations of agents creates non-permissive conditions for the reproduction of HSV-1 and opens up new real possibilities for controlling human herpesvirus infection.