Broad-spectrum antiviral diazadispiroalkane core molecules - block attachment and cell-to-cell spread of Herpesviruses

We demonstrated that the diazadispiroalkane derivatives, 11826091 and 11826236, exhibit potent antiherpetic activity against the herpesvirus species, murine cytomegalovirus (MCMV) and herpes simplex virus type 1 (HSV-1), as well as a human CMV (HCMV) clinical isolate. The low cytotoxicity was underlined by the LD₅₀ determination in mice. We have shown that inhibition occurs at an early stage of infection. Both small molecules probably interact electrostatically with sulfated glycosaminoglycans (GAGs) of proteoglycans on target cells resulting in blockage of adsorption sites for herpesvirus glycoprotein. Moreover, both compounds showed significant effects against the cell-associated viral spread of HSV-1 and HCMV. Interestingly, 11826091 and 11826236 also reduced immediate early gene expression in HCMV and HSV-1 infected cells in a dose-dependent manner. Overall, our results support the high potency of two diazadispiroalkane derivatives as inhibitors of viral entry and provide requirements for the following development of a new approach of a broad antiviral therapy.

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