Despite careful donor selection and extensive laboratory testing, a small risk of virus transmission by transfusion still exists. Additional efforts in donor selection and infectious disease testing may not substantially reduce this risk. However, the development of virus inactivation protocols for cellular components of blood should provide an additional level of safety. Current efforts in this arm have failed to meet the overall needs of transfusion medicine. The goal of this research is to use the techniques of rational drug design to develop novel compounds which photoinactivate both extracellular and intracellular viruses while permitting the maintenance of the in vitro properties of red cell and platelet suspensions during routine storage under blood banking conditions. Novel compounds will be developed which can form covalent adducts to nucleic acids upon illumination with visible light. To achieve this goal, carefully selected chemical modifications will be made to three families of photoactive compounds which already possess some of the desired characteristics: the phenothiazine family, the gilvocarcin family, and a family of photoactivatable organic metal complexes. Novel compounds will be purified and screened for their ability to photoinactivate bacteriophage and form covalent adducts with nucleic acids. Promising candidates will then be tested for their potential to inactivate extracellular and intracellular mammalian and human viruses. For compounds with substantial antiviral activity against mammalian viruses, the in vitro storage properties of phototreated red cell and platelet suspensions will be characterized. Finally, mutagenicity testing (Ames) will be carried out on those compounds with promising antiviral activity and minimal adverse influence on red cell and platelet in vitro properties.
