Smallpox (variola major) continues to be a significant potential bioterror threat and preparation is of high priority because the consequences of a bioterror attack could be dire. Although adequate supplies of vaccine are available, over 40 million people are not good candidates for vaccination because of skin diseases, immunosuppression and heart disease. A safe, effective oral drug could be an important addition to the country's biodefense armamentarium. We previously discovered orally active analogs of cidofovir (CDV) which prevent death in lethal challenge models of poxvirus disease. One of these, hexadecyloxypropyl-CDV (HDP-CDV), has been chosen by NIAID for development with Phase I clinical trials targeted for early 2005. HDP-CDV and similar compounds prevent mortality and eliminate virus from liver and spleen in cowpox, vaccinia and ectromelia. However, HDP-CDV does not reduce lung viral titers, a potential drawback, since recovering persons might still harbor a million pfu of virus/gm of lung, raising the question of whether virus could still be transmitted by coughing. We have discovered that esterification of CDV with 1-O-octadecyl-2-O-benzyl-sn-glycerol (ODBG-) produces a very active antiviral which delivers 10 times more drug to lung than HDP-CDV. Lung-targeted antivirals like ODBG-CDV might solve the problem of high poxvirus titers in lung, while still providing excellent protection against lethal poxvirus challenge. This R21 project will explore this novel new type of prodrug; ODBG- analogs of CDV and the more active (S)-HPMPA and PMEG derivatives will be synthesized and evaluated. Their in vitro antiviral activity against cowpox, vaccinia, ectromelia, monkeypox and variola will be assessed and their cellular metabolism, oral pharmacokinetics and short term toxicology will be examined in mice. Dosing regimens will be developed and their activity will be compared with HDP-CDV in oral treatment of cowpox, vaccinia and ectromelia lethal challenge models in mice. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI064615-02
Application #
7082071
Study Section
Special Emphasis Panel (ZRG1-DDR (01))
Program Officer
Greenstone, Heather Lea
Project Start
2005-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$282,013
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
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Quenelle, Debra C; Collins, Deborah J; Herrod, Bridgett P et al. (2007) Effect of oral treatment with hexadecyloxypropyl-[(S)-9-(3-hydroxy-2- phosphonylmethoxypropyl)adenine] [(S)-HPMPA] or octadecyloxyethyl-(S)-HPMPA on cowpox or vaccinia virus infections in mice. Antimicrob Agents Chemother 51:3940-7
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Dal Pozzo, Fabiana; Andrei, Graciela; Lebeau, Ilya et al. (2007) In vitro evaluation of the anti-orf virus activity of alkoxyalkyl esters of CDV, cCDV and (S)-HPMPA. Antiviral Res 75:52-7

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