pyrimidinones and Virus-Diseases

Topics: Animals; Antifungal Agents; Antineoplastic Agents; Antiviral Agents; Histamine H1 Antagonists; Humans; Mycoses; Neoplasms, Experimental; Pyrimidinones; Virus Diseases

The amphipathic dye, merocyanine 540 (MC540), which preferentially photosensitizes enveloped viruses and virus-infected cells, is currently being evaluated in preclinical models as a blood sterilizing agent. In this communication, we report on an initial analysis of the site and nature of MC540-mediated photodynamic damages to human herpes simplex virus type 1 and human cytomegalovirus. The comigration of dye molecules and virions on a gel filtration column, the red-shift of the fluorescence emission spectrum of virus-containing fractions, and the distribution of MC540-treated virions in an aqueous two-phase partition system were indicative of MC540 binding to the enveloped viruses and localizing in a lipophilic environment (most likely the viral envelope). Fluorescence quenching and fluorescence resonance energy transfer experiments suggested that both dye monomers and dimers were capable of partitioning into the lipid bilayer of the viral envelope. Adsorption and penetration assays and immunohistochemical analyses of viral antigen expression showed that MC540-sensitized irradiation interfered with early phases of the infectious process, the adhesion to the host cell, the penetration of the host cell, and the translocation of the virus into the nucleus of the host cell. The inactivation of viruses was inhibited if oxygen in the medium was displaced by argon, enhanced if air was displaced by pure oxygen or if water was replaced by deuterium oxide. This suggested that the MC540-sensitized photoinactivation of enveloped viruses is an oxygen-dependent process and that singlet oxygen is one but not necessarily the only mediator of the antiviral effects of MC540.

Topics: Animals; Cell Membrane; Cells, Cultured; Cysteamine; Dithiothreitol; Glutathione; Humans; In Vitro Techniques; Oxidation-Reduction; Photochemotherapy; Pyrimidinones; Receptors, Virus; Simplexvirus; Vero Cells; Virus Diseases

Two viral inactivation methods suggested for use with cellular blood products have been evaluated as to their effects on platelets. In the first study, it was proposed that pulsed laser-ultraviolet radiation (UVB) at 308 nm could favor photodamage to UVB-sensitive viral nucleic acid with minimal effects on blood platelets. A "window of efficacy" was observed with UVB doses of 10.5-21.5 J/cm2 at which 4-6 log10 poliovirus were inactivated while platelets were relatively tolerant. However, this "window" occurred only with low-intensity UVB radiation (less than or equal to 0.25 MW/cm2). Damage to platelet proteins, evident at high laser intensities, was probably due to multiple photon excitation of amino acids. In the second study, platelets and viruses were treated with the photosensitizer, merocyanine 540 (MC 540) (less than or equal to 24 micrograms/ml), and visible light (450-600 nm) (less than or equal to J/cm2). Activation of washed platelets by dye/light treatment resulted in a spontaneous release of serotonin, spontaneous aggregation, and marked morphological changes. Increasing concentrations of albumin in the suspension medium protected against dye-mediated photodamage to platelets, but also significantly reduced the antiviral activity of MC 540 and light. These results illustrate the relative sensitivities of platelets and viruses to two inactivation methods and the difficulty in optimizing inactivation of viruses and preservation of platelet function in a protein-rich medium.

Topics: Blood; Blood Platelets; Blood Proteins; DNA Damage; Humans; Lasers; Photochemistry; Platelet Activation; Pyrimidinones; Radiation-Sensitizing Agents; Ultraviolet Rays; Virus Diseases; Virus Physiological Phenomena; Virus Replication; Viruses

Interferon induction and antiviral activity was discovered with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone. An analogue study incorporating a series of 2-amino-5-substituted-6-arylpyrimidinones revealed that the most potent interferon inducers were mono- and difluorophenyl analogues. These same analogues were also potent antiviral agents against Semliki Forest virus and herpes simplex type 1. In addition the monomethoxyphenyl analogues were potent antiviral agents but weak interferon inducers. Relatively modest structural changes led to dramatic changes in bioactivity. There was a relatively poor correlation between levels of circulating interferons induced and systemic antiviral activity.

Topics: Animals; Chemical Phenomena; Chemistry; Female; Halogens; Herpes Simplex; Interferon Inducers; Interferon Type I; Interferon-gamma; Male; Mice; Mice, Inbred ICR; Pyrimidinones; Semliki forest virus; Structure-Activity Relationship; Togaviridae Infections; Virus Diseases

Topics: Animals; Cytosine; Female; Immunity; Interferon Inducers; Interferons; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Pyrimidines; Pyrimidinones; Virus Diseases