Nucleoside Phosphonate Analogs for the Treatment of Adenoviral Infection

描述(由申请人提供)：腺病毒对免疫受损的患者，包括成人和儿童患者，可能是一个重大的健康风险。尤其是在儿科患者中，与腺病毒感染相关的并发症包括肺炎、尿路感染和肝炎。在军事环境中，腺病毒在国防部基础新兵训练设施中是地方性疾病，并经常引起热性呼吸道疾病的流行。一种有效对抗4型和7型的腺病毒疫苗已获得FDA的许可，但其未来的长期供应尚不确定，也没有预防其他类型的腺病毒的疫苗，包括14型，它已在基础新兵和平民中导致致命的呼吸道疾病。目前，西多福韦是唯一一种显示出对腺病毒感染有效的许可药物。然而，西多福韦只能静脉给药，由于肾脏毒性，其使用进一步受到限制。因此，开发和批准治疗腺病毒感染的改良药物对公共卫生界具有非常重要的意义。我们开发了一种平台技术，旨在改善核苷酸磷酸盐药物西多福韦(CDV)和HPMPA的口服吸收，使它们成为有效的抗腺病毒口服治疗剂。在项目的第一阶段，我们建议合成一系列新的CDV和HPMPA前体药物，并评估它们对一系列医学上相关的腺病毒血清型的抗腺病毒活性。还将测试这些类似物的药代动力学特征，包括吸收和分布。这项工作将为开发一种有效的抗腺病毒口服制剂奠定科学基础，腺病毒与急性呼吸道疾病有关，并在免疫受损的人中传播感染。在这个项目中，我们与南加州大学的Charles McKenna教授(模拟设计和合成)和Lovelace呼吸研究所的Adriana Kajon博士(病毒学研究)建立了合作关系。

DESCRIPTION (provided by applicant): Adenovirus can be a significant health risk for immune-compromised patients, both adult and pediatric patients. In pediatric patients in particular, complications associated with adenoviral infection include pneumonia, urinary infections and hepatitis. In the military setting, adenoviruses are endemic in Department of Defense basic recruit training installations and cause frequent epidemics of febrile respiratory disease. An adenovirus vaccine effective against types 4 and 7 is licensed by the FDA, but its future long-term availability is uncertain and there is no vaccine for the prevention of other adenovirus types, including type 14 which has caused fatal respiratory disease in basic recruits as well as in civilian populations. Currently, cidofovir is the only licensed drug that has shown efficacy against adenovirus infections. However, cidofovir can only be given intravenously and its use is further limited due to renal toxicity. Therefore, development and licensure of improved drugs to treat adenovirus infection is of high importance to the public health community. We have developed a platform technology designed to improve the oral absorption of the nucleotide phosphonate drugs, cidofovir (CDV) and HPMPA, such that they will be effective anti-adenoviral oral therapeutic agents. In the phase 1 portion of the project, we propose to synthesize a novel series of CDV and HPMPA prodrugs and evaluate their anti-adenoviral activity against a range of medically relevant adenoviral serotypes. These analogs will also be tested for their pharmacokinetic profile, including absorption and distribution. This work will lay the scientific foundation for development of an effective, oral agent against adenovirus that is implicated in acute respiratory disease and disseminating infection in immune-compromised individuals. For this project, we have established collaborations with Prof. Charles McKenna (analog design and synthesis) at the University of Southern California and Dr. Adriana Kajon (virological studies) at the Lovelace Respiratory Research Institute.