The cerium , lanthanum , and neodymium complexes with 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (warfarin) (W) and 3,3′-benzylidenebis[4-hydroxycoumarin] (1) were synthesized and studied for the first time for cytotoxicity (on MT-2 cells) and as anti-HIV agents under acute and chronic infection. The complexes were characterized by different physicochemical methods: mass spectrometry, NMR, NMR, and IR spectroscopy. The spectra of the complexes were interpreted on the basis of comparison with the spectrum of the free ligands. Anti-HIV effect of the complexes/ligands was measured in MT-2 cells by microtiter infection assay. Detection of endogenous reverse transcriptase (RT) activity and RT processivity by PCR indicative for proviral DNA synthesis demonstrated that anti-HIV activity has not been linked to early stages of viral replication. No effect on late steps of viral replication has been found using cells chronically producing HIV-1LAI virus. demonstrated anti-HIV activity (IC50=21.4 μM) close to maximal nontoxic concentration. , , and demonstrated limited anti-HIV potency, so none of the complexes seems appropriate to be used in clinic. Further targeting of HIV-1 inhibition by is under progress.

The cytotoxicity and the antivirus activity of native hemocyanin, RtH, derived from the Bulgarian marine mollusk Rapana thomasiana and its structural isoform, RtH2, against HSV replication was evaluated on three HSV strains Ð two wt strains, TM (HSV 1) and Bja (HSV 2), and one ACV R mutant with tk gene mutation, DD (HSV 2). The experiments were performed on continuous RD 64 cells and three HSV 1 and HSV 2 strains were used, two mutants sensitive to acyclovir and one resistant mutant.Both compounds were found to be effective inhibitors of wt HSV replication. Both compounds did not exhibit any effect on the infectious virus yield on ACV R mutant. The most promising, active and selective, anti-HSV agent, especially to genital herpes virus, was found to be the functional unit of native hemocyanin Ð RtH2. RtH2 did not induce apoptosis/ necrosis 8 h after virus infection and the target of its action, was found to be the viral but not the host cell DNA.

No abstract

Pharmacological induction of low deoxyribonucleoside triphosphate (dNTP) levels in virus-infected cells could result in an increased antiviral effectiveness of some selective antiviral nucleoside analogues. That could be exploited as a new combined strategy in the treatment of herpes virus infections. From this point of view the alteration of antiherpes activity of acyclovir (ACV) in combination with mizoribine (N′-[β-d-ribofuranosyl]-5-hydroxyimidazole-4-carboxamide) (MZR), an inhibitor which lowers the intracellular pool of dGTP, was studied. MZR applied alone at non-toxic concentrations had no effect on herpes simplex virus type 1 (HSV-1) replication in human embryonic skin-muscle fibroblasts (HESMF). The combination of MZR and ACV acts synergistically, as measured by the virus yield assay in the above mentioned system. The potentiating effect of MZR on the anti-HSV-1 activity of ACV was reversed by guanosine (Guo). In this case dGTP could be considered as the “key metabolite” responsible for the higher effectivity of the combination of drugs.

The thymidine kinase inducing ability of 104 strains of herpes simplex virus was studied comparatively. A pronounced relationship was established between induction of the enzyme and the serotype of the strains. As a rule, the strains of serotype 2 are weaker inducer of dThd- and dCyd-kinase activity than serotype 1 strains. A certain parallelism exists between induction of both enzymes, however the activity of the thymidine kinase increases after infection with herpes simplex virus 4--5 times more than that of the dCyd-kinase. Adaptation of the strains to cell cultures only slightly modifies the inducing ability of the herpes simplex virus strains. The thymidine kinase activity induced by HSV-1 and HSV-2 differ from each other and are different from the cell enzyme with respect to their thermal stability at 40 degrees C. These differences are expressed more clearly in the presence of 480 muM dThdMP during inactivation. dThdMP stabilizes the type 1 but not the type 2 enzyme.