Human cytomegalovirus (HCMV) retinitis in an important clinical problem in AIDS patients with CD4+ cell counts <50. The overall goal of this project is to design, evaluate and optimize novel lipid prodrugs with activity against HSV and HCMV for use as a local intravitreal therapy for viral retinitis. The project is a collaboration between the laboratories of Dr. Karl Hostetler (antiviral drug synthesis and in vitro antiviral evaluations) and Dr. William Freeman (animal models of toxicology, pharmacokinetics and viral retinitis). Dr. Hostetler has prepared lipid prodrugs of acyclovir (ACV), ACV diphosphate dimyristoylglycerol (ACVDP-DMG) which exhibited a 9-fold increased activity against HCVM and provided for 3-4 week retention times above its EC90 after a single intravitreal injection. The procedures are also applicable to ganciclovir (GCV), which will be studied as part of this project. In addition, a novel prodrug of foscarnet (PFA), octadecylglycero-PFA, was discovered by Dr. Hostetler s group which was 100 times more active than PFA in HCVM-infected cells and 43 times more active than PFA in HSV-1 infected cells.
The Specific Aims are: 1) by structure-activity determinations in HSV-1 and HCMV infected cells, the investigators plan to attempt to optimize the prodrug structures for intravitreal use in viral retinitis; 2) toxicity, intravitreal clarity and pharmacokinetics of the lipid prodrugs will be analyzed in rabbits and guinea pigs. Liposomal and micellar formulations of the prodrugs of ACV, PFA and GCV will be compared when possible to find the best way of delivering these compounds over time, and 3) the antiviral efficacy of the most promising compounds administered by direct intravitreal injection will be assessed in HSV-1 retinitis in rabbits.
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