Abstract

The overall goal of this project is to systematically evaluate prodrug strategies for targeting larger amounts of various antiviral compounds to important tissue reservoir of disease: the lymphatic system in AIDS and the liver in hepatitis B. The investigators intend to identify optimal prodrug strategies for targeting the lymphatic tissue reservoir of HIV and to find the optimal liposome formulations and mode of administration by studying lymph node and tissue distribution of radiolabeled antiviral prodrugs. Optimized prodrug strategies will be tested in animal models of hepatitis B, specifically the woodchuck hepatitis model, and in models of retro viral disease in mice. Additionally the applicants plan to systematically evaluate various lipid prodrug HBV antivirals in vitro in 2.2.15 cells to find the most active chemical forms. The investigators have already found that certain lipid analogs of acyclovir and azidothymidine are much more active than the free nucleotides in 2.2.15 cells. The biologic and metabolic basis for the greatly increased activity will be evaluated to aid in design of better antiviral agents. Finally, the researchers will explore the activity of the optimized liver-targeted lipid prodrug antivirals in woodchuck HBV; and their toxicity will be evaluated in rodents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM024979-18
Application #
2174365
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1978-04-01
Project End
1998-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
18
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Beadle, J R; Kini, G D; Aldern, K A et al. (1998) Alkylthioglycerol prodrugs of foscarnet: synthesis, oral bioavailability and structure-activity studies in human cytomegalovirus-, herpes simplex virus type 1- and human immunodeficiency virus type 1-infected cells. Antivir Chem Chemother 9:33-40
Hostetler, K Y; Beadle, J R; Kini, G D et al. (1997) Enhanced oral absorption and antiviral activity of 1-O-octadecyl-sn-glycero-3-phospho-acyclovir and related compounds in hepatitis B virus infection, in vitro. Biochem Pharmacol 53:1815-22
Taskintuna, I; Banker, A S; Flores-Aguilar, M et al. (1997) Evaluation of a novel lipid prodrug for intraocular drug delivery: effect of acyclovir diphosphate dimyristoylglycerol in a rabbit model with herpes simplex virus-1 retinitis. Retina 17:57-64
Kini, G D; Beadle, J R; Xie, H et al. (1997) Alkoxy propane prodrugs of foscarnet: effect of alkyl chain length on in vitro antiviral activity in cells infected with HIV-1, HSV-1 and HCMV. Antiviral Res 36:43-53
Schlame, M; Hostetler, K Y (1997) Cardiolipin synthase from mammalian mitochondria. Biochim Biophys Acta 1348:207-13
Kini, G D; Hostetler, S E; Beadle, J R et al. (1997) Synthesis and antiviral activity of 1-O-octadecyl-2-O-alkyl-sn-glycero-3-foscarnet conjugates in human cytomegalovirus-infected cells. Antiviral Res 36:115-24
Korba, B A; Xie, H; Wright, K N et al. (1996) Liver-targeted antiviral nucleosides: enhanced antiviral activity of phosphatidyl-dideoxyguanosine versus dideoxyguanosine in woodchuck hepatitis virus infection in vivo. Hepatology 23:958-63
Xie, H; Voronkov, M; Liotta, D C et al. (1995) Phosphatidyl-2',3'-dideoxy-3'-thiacytidine: synthesis and antiviral activity in hepatitis B-and HIV-1-infected cells. Antiviral Res 28:113-20
Shakiba, S; Freeman, W R; Flores-Aguilar, M et al. (1995) Antiviral effect in human cytomegalovirus-infected cells, pharmacokinetics, and intravitreal toxicology in rabbits of acyclovir diphosphate dimyristoylglycerol. Antimicrob Agents Chemother 39:1383-5
Hostetler, K Y; Richman, D D; Sridhar, C N et al. (1994) Phosphatidylazidothymidine and phosphatidyl-ddC: assessment of uptake in mouse lymphoid tissues and antiviral activities in human immunodeficiency virus-infected cells and in Rauscher leukemia virus-infected mice. Antimicrob Agents Chemother 38:2792-7

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