[Carboxy mimetic derivatives of nucleic acid polymeric backbones inhibiting human cytomegalovirus. 1. In vitro microbicidal effect]

Abstract

The artificial polycarboxyacidic compounds (PC), imitating the principle of furan-derived and negatively charged structures alternating in the polymeric backbone of nucleic acids, previously explored as interferon inductors and stimulators of antiviral immunity in vivo, were modified by the side groups to amplify the direct antiviral potency in vitro and investigated in the cell culture model of human diploid fibroblasts infected with human cytomegalovirus (CMV) in a microbicidal scheme. Reconstruction from the PC to membrane potent compounds (MPC) was carried out by covalent modification with lipotropic pharmacophores (of cage-hydrocarbon structures similar to rimantadine or camphor-like terpenoids), as well as by conversion of the carboxy groups to sulfate-anionic derivates, related to the CMV sensitive heparansulfate receptor (HSR) of the cells. Both the factors of the MPC structure-functional modulation (lipotropic and anionic) were found to be effective tools for amplification of the microbicidal activity. The maximum inhibitory effect against CMV and minimum cytotoxicity (with the best selectivity, the chemotherapeutic index of > or = 3000-5000) were achieved mainly through increasing the anionic groups content, elevating the MPC negative charge to the level comparable with one of the like charged viral genome and HSR. In relation with the previously found anti-HIV efficacy of the same MPCs in analogous experimental models and in view of the fact that CMV is one of the most dangerous opportunistic co-factors of HIV/AIDS pathogenesis, the obtained data can be used as a basis for further development of new generation microbicides, promising for combined prevention of sexually transmitted infections.