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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY011832-03S1
Application #
6262159
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Program Officer
Dudley, Peter A
Project Start
1997-04-01
Project End
2000-07-31
Budget Start
1999-04-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
2000
Total Cost
$122,311
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Wang, Haiyan; Chhablani, Jay; Freeman, William R et al. (2011) Intraocular safety and pharmacokinetics of hexadecyloxypropyl-cidofovir (HDP-CDV) as a long-lasting intravitreal antiviral drug. Invest Ophthalmol Vis Sci 52:9391-6
Choo, Hyunah; Beadle, James R; Kern, Earl R et al. (2007) Antiviral activities of novel 5-phosphono-pent-2-en-1-yl nucleosides and their alkoxyalkyl phosphonoesters. Antimicrob Agents Chemother 51:611-5
Choo, Hyunah; Beadle, James R; Chong, Youhoon et al. (2007) Synthesis of the 5-phosphono-pent-2-en-1-yl nucleosides: a new class of antiviral acyclic nucleoside phosphonates. Bioorg Med Chem 15:1771-9
Beadle, James R; Wan, William B; Ciesla, Stephanie L et al. (2006) Synthesis and antiviral evaluation of alkoxyalkyl derivatives of 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine against cytomegalovirus and orthopoxviruses. J Med Chem 49:2010-5
Ruiz, Jacqueline C; Aldern, Kathy A; Beadle, James R et al. (2006) Synthesis and antiviral evaluation of alkoxyalkyl esters of phosphonopropoxymethyl-guanine and phosphonopropoxymethyl-diaminopurine. Antivir Chem Chemother 17:89-95
Keith, Kathy A; Wan, William B; Ciesla, Stephanie L et al. (2004) Inhibitory activity of alkoxyalkyl and alkyl esters of cidofovir and cyclic cidofovir against orthopoxvirus replication in vitro. Antimicrob Agents Chemother 48:1869-71
Smee, Donald F; Wong, Min-Hui; Bailey, Kevin W et al. (2004) Effects of four antiviral substances on lethal vaccinia virus (IHD strain) respiratory infections in mice. Int J Antimicrob Agents 23:430-7
Bidanset, Deborah J; Beadle, James R; Wan, W Brad et al. (2004) Oral activity of ether lipid ester prodrugs of cidofovir against experimental human cytomegalovirus infection. J Infect Dis 190:499-503
Quenelle, Debra C; Collins, Deborah J; Wan, W Brad et al. (2004) Oral treatment of cowpox and vaccinia virus infections in mice with ether lipid esters of cidofovir. Antimicrob Agents Chemother 48:404-12
Kern, Earl R; Collins, Deborah J; Wan, W Brad et al. (2004) Oral treatment of murine cytomegalovirus infections with ether lipid esters of cidofovir. Antimicrob Agents Chemother 48:3516-22

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