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.
We have previously reported that (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, or (S)-HPMPA, is active in vitro against cowpox virus (CV) and vaccinia virus (VV) but is not active orally in animals. However, the ether lipid esters of (S)-HPMPA, hexadecyloxypropyl-[(S)-HPMPA] [HDP-(S)-HPMPA] and octadecyloxyethyl-[(S)-HPMPA] [ODE-(S)-HPMPA], had significantly enhanced activity in vitro and are orally bioavailable in mice. In the current study, HDP-(S)-HPMPA and ODE-(S)-HPMPA were prepared in water and administered once daily by oral gavage to mice at doses of 30, 10, and 3 mg/kg of body weight for 5 days beginning 24, 48, or 72 h after inoculation with CV or VV. Oral HDP-(S)-HPMPA and ODE-(S)-HPMPA were both highly effective (P < 0.001) at preventing mortality due to CV at 30 mg/kg, even when treatments were delayed until up to 72 h postinfection. ODE-(S)-HPMPA or HDP-(S)-HPMPA were also highly effective (P < 0.001) at preventing mortality in mice infected with VV at 30 mg/kg when treatments were delayed until to 48 or 72 h postinfection, respectively. Protection against both viruses was associated with a significant reduction of virus replication in the liver, spleen, and kidney but not in the lung. These data indicate that HDP-(S)-HPMPA and ODE-(S)-HPMPA are active when given orally against lethal CV and VV infections in mice, and further evaluation is warranted to provide additional information on the potential of these orally active compounds for treatment of human orthopoxvirus infection.
Quenelle
Debra C
DC
Department of Pediatrics, The University of Alabama at Birmingham, School of Medicine, CHB 128, 1600 6th Avenue South, Birmingham, AL 35233, USA. DQuenelle@peds.uab.edu
Collins
Deborah J
DJ
Herrod
Bridgett P
BP
Keith
Kathy A
KA
Trahan
Julissa
J
Beadle
James R
JR
Hostetler
Karl Y
KY
Kern
Earl R
ER
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015605:Cowpox / Q000188:drug therapy* / Q000821:virology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D051379:Mice; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D014616:Vaccinia virus / Q000187:drug effects*
D000998:Antiviral Agents; D063065:Organophosphonates; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine