Lung-Targeted Poxvirus Antivirals

描述（由申请人提供）：天花（天花大）仍然是一个重大的潜在生物恐怖威胁和准备是高度优先，因为生物恐怖袭击的后果可能是可怕的。虽然疫苗供应充足，但有4 000多万人因皮肤病、免疫抑制和心脏病而不适合接种疫苗。一种安全、有效的口服药物可能是该国生物防御设施的重要补充。我们先前发现西多福韦（CDV）的口服活性类似物，可预防痘病毒病致死攻击模型中的死亡。其中之一，十六烷氧基丙基-CDV（HDP-CDV），已被NIAID选择用于2005年初的I期临床试验。HDP-CDV和类似的化合物可防止死亡，并可消除牛痘、牛痘和鼠痘中肝脏和脾脏的病毒。然而，HDP-CDV不会降低肺病毒滴度，这是一个潜在的缺点，因为恢复中的人可能仍然携带一百万pfu病毒/gm肺，这提出了病毒是否仍然可以通过咳嗽传播的问题。我们已经发现，CDV与1-O-十八烷基-2-O-苄基-sn-甘油（ODBG-）的酯化产生非常活性的抗病毒剂，其向肺递送的药物比HDP-CDV多10倍。肺靶向抗病毒药物如ODBG-CDV可能解决肺中高痘病毒滴度的问题，同时仍然提供针对致死性痘病毒攻击的优异保护。该R21项目将探索这种新型的前药;将合成和评价CDV的ODBG类似物和更有活性的（S）-HPMPA和PMEG衍生物。将评估它们对牛痘、牛痘、肢脱病、猴痘和天花的体外抗病毒活性，并将在小鼠中检查它们的细胞代谢、口服药代动力学和短期毒理学。将开发给药方案，并将其活性与HDP-CDV在小鼠牛痘、牛痘和鼠肢畸形致死性攻毒模型中的经口治疗进行比较。

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.