[Antiviral activity of polycarboxylic substances modified by cage hydrocarbon and sulfoacid pharmacophors against cytomegalovirus infection in vitro]

Abstract

Human cytomegalovirus (CMV) infection (CMVI) results in lethal risks at the immunodeficiency status, including the HIV co-infection. Carboxy-mimickers of the polymeric backbone of nucleic acids, potential agonists and antagonists of the virus genome were developed as promising candidates for the antiviral protective agents. In parallel with stimulation of antiviral immunity the mimickers derived membrane potent compounds (MPC), were shown to be able to prevent directly and efficiently the cell infection by various strains of the human immunodeficiency virus (HIV) [Antibiotics and Chemother 2003; 48: 2:29-41; 5:7-15]. The paper presents new data and discussion of the results on investigation of the MPC, modified by the previously designed adamantane or norbornene and by the recently applied sulfoacidic pharmacophores in the experimental model of CMVI in vitro (human diploid fibroblast cells). Eight substances with various ratios of theabove mentioned cage-hydrocarbon and/or anion pharmacophores in the macromolecule were tested and active MPC modifications were detected which efficiently inhibited the CMVI with high indexes of selectivity up to 250, 4286 and 7500 in prophylactic, therapeutic and viricidal experimental schemes respectively. Modulating influence of the lipotropic (cage-hydrocarbon) pharmacophores on the anti-CMV activity was observed only in the viricidal and prophylactic experimental schemes, in which the lipid membranes of the cells and/or virus envelopes were involved. Still, the dominant role in the antiviral activity of MPC in all the experimental schemes was played by the sulfoacid-anionic chemical structure modulation. By increasing the density of the negative charge of the macromolecules to the levels comparable with the charge of the genome molecules, theanionic modification evidently amplified the potential of the antagonistic competition of the synthetic MPC with the virus genome, thus impairing the virus-specific interactions. The most promising compounds AS-688 and AS-678/-679 were selected for further investigation of the mechanisms of the anti-CMV and anti-HIV activity.