Abstract
Hexadecyloxypropyl-cidofovir (HDP-CDV) is a novel ether lipid conjugate of (S)-1-(3-hydroxy-2-phosphonoylmethoxypropyl)-cytosine (CDV) which exhibits a remarkable increase in antiviral activity against orthopoxviruses compared with CDV. In contrast to CDV, HDP-CDV is orally active and lacks the nephrotoxicity of CDV itself. Increased oral bioavailability and increased cellular uptake is facilitated by the lipid portion of the molecule which is responsible for the improved activity profile. The lipid portion of HDP-CDV is cleaved in the cell, releasing CDV which is converted to CDV diphosphate, the active metabolite. HDP-CDV is a highly effective agent against a variety of orthopoxvirus infections in animal models of disease including vaccinia, cowpox, rabbitpox and ectromelia. Its activity was recently demonstrated in a case of human disseminated vaccinia infection after it was added to a multiple drug regimen. In addition to the activity against orthopoxviruses, HDP-CDV (CMX001) is active against all double stranded DNA viruses including CMV, HSV-1, HSV-2, EBV, adenovirus, BK virus, orf, JC, and papilloma viruses, and is under clinical evaluation as a treatment for human infections with these agents.
Highlights
Smallpox was a major cause of mortality worldwide until it was eliminated by the WHO vaccination program in the late 1970s [1]
Cidofovir Identified as an Effective Inhibitor of Poxviruses (S)-1-(3-hydroxy-2-phosphono-methoxypropyl)adenine (HPMPA) and (S)-1-(3-hydroxy-2phosphonomethoxypropyl)-cytosine (HPMPC, cidofovir) are acyclic nucleoside phosphonate antivirals first described by Holy and De Clercq [6,7]
A patient who was vaccinated for smallpox and later found to have leukemia developed a disseminated vaccinia virus infection
Summary
Smallpox was a major cause of mortality worldwide until it was eliminated by the WHO vaccination program in the late 1970s [1] It was a disease transmitted by aerosol which caused 30% mortality and disfiguring skin lesions in survivors. 2. Cidofovir Identified as an Effective Inhibitor of Poxviruses (S)-1-(3-hydroxy-2-phosphono-methoxypropyl)adenine (HPMPA) and (S)-1-(3-hydroxy-2phosphonomethoxypropyl)-cytosine (HPMPC, cidofovir) are acyclic nucleoside phosphonate antivirals first described by Holy and De Clercq [6,7]. Cidofovir Identified as an Effective Inhibitor of Poxviruses (S)-1-(3-hydroxy-2-phosphono-methoxypropyl)adenine (HPMPA) and (S)-1-(3-hydroxy-2phosphonomethoxypropyl)-cytosine (HPMPC, cidofovir) are acyclic nucleoside phosphonate antivirals first described by Holy and De Clercq [6,7] Both HPMPA and HPMPC were shown to have antiviral activity in the vaccinia virus mouse tail lesion model [7,8]. An oral drug with less toxicity which could be delivered from a stockpile and self administered would be much more desirable for emergency use
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