Lung-Targeted Poxivirus Antivirals

描述（由申请人提供）：天花（主要天花）仍然是一个重要的潜在生物恐怖威胁，并且准备工作是高度优先的，因为生物恐怖袭击的后果可能是可怕的。虽然有充足的疫苗供应，但由于皮肤病、免疫抑制和心脏病，4 000多万人不是很适合接种疫苗的人选。一种安全有效的口服药物可能是该国生物防御装备的重要补充。我们以前发现口服活性的西多福韦（CDV）类似物可以预防痘病毒疾病致命攻击模型中的死亡。其中一种疫苗十六进基氧丙基cdv （HDP-CDV）已被NIAID选中进行开发，计划于2005年初进行I期临床试验。HDP-CDV和类似的化合物防止死亡，并消除牛痘、牛痘和羊痘的肝脏和脾脏病毒。然而，HDP-CDV不会降低肺部病毒滴度，这是一个潜在的缺点，因为康复的人可能仍然携带100万pfu /gm的病毒，这就提出了病毒是否仍然可以通过咳嗽传播的问题。我们发现CDV与1- o -十八烷基-2- o -苄基-森-甘油（ODBG-）的酯化反应产生了一种非常活跃的抗病毒药物，其向肺输送的药物是HDP-CDV的10倍。肺靶向抗病毒药物如ODBG-CDV可能解决肺中痘病毒滴度高的问题，同时仍然对致命的痘病毒攻击提供良好的保护。这个R21项目将探索这种新型的前药；将合成并评价CDV的ODBG-类似物以及活性更高的(S)- hpmpa和PMEG衍生物。将评估它们对牛痘、牛痘、羊痘、猴痘和天花的体外抗病毒活性，并在小鼠体内研究它们的细胞代谢、口服药代动力学和短期毒理学。将制定给药方案，并将其与HDP-CDV在口服治疗牛痘、牛痘和羊痘致死性攻毒模型小鼠中的活性进行比较。

DESCRIPTION (provided by applicant): 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.