Current therapies for CMV retinitis (CMV-R) are far from optimal. Although the incidence of CMV-R has declined since the advent of HAART, many AIDS experts believe that it will become more frequent in the future. This is because of the increased prevalence of persons living with HIV infection (nearly 1 million Americans), the 5 percent to 10 percent estimated annual rate of development of resistance to HAART, as well as the fact that substantial percentages of unselected patients fail to respond to HAART. Thus, it would be prudent to develop better methods for treating CMV-R. The overall goal of the re-revised competing renewal of EY1 1832 is to design, evaluate and optimize prodrugs with activity against CMV for an oral therapy for CMV-R. During the first 3 years, derivatives of ganciclovir (GCV) and foscarnet (PFA) were found to be active for 4 weeks or longer after a single intravitreal injection. An oral prodrug of GCV was discovered which is active against murine CMV, acute HSV-1 infection in mice, and in SCID-hu mice with HCMV-infected human retinal implants. Recently 1 -O-hexadecylpropanediol-3-cCDV, a highly active analog of cyclic Cidofovir (cCDV) has been synthesized and found to have a subnanomolar IC50 against HCMV and a selectivity index of >50,000. The compound is similar in design to orally bioavailable prodrugs of GCV. Generally stated, the specific aims of the re-revised proposal are to carry out structure-activity assessments of the in vitro activity and selectivity of lipid prodrugs of GCV and CDV designed and optimized for oral therapy of HCMV infection and to evaluate the safety parameters in vitro and in vivo and efficacy in HCMV retinitis in SCID-mice in vivo. Oral pharmacokinetics and toxicology of selected GCV and CDV prodrugs will be assessed in rodents, followed by testing for oral efficacy in SCID-hu mice with human HCMV-infected retinal implants or in murine CMV infection in mice. Since many AIDS experts believe that CMV-retinitis has reached a temporary nadir and will increase in the future, this research has direct health-related significance both to those Americans living with HIV infection and to organ transplant patients at risk for CMV disease because of their need for immunosuppresive drugs to prevent organ rejection.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011832-06
Application #
6524937
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Dudley, Peter A
Project Start
1997-04-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2004-08-31
Support Year
6
Fiscal Year
2002
Total Cost
$307,600
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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