GENOME TARGETED INHIBITORS OF RETROVIRUSES

描述：(改编自申请者摘要)主旨 这个应用程序继续以非翻译的不变量为目标 HIV基因组5‘端有专门设计的结构域 聚酰胺核酸(PNA)及其衍生物。的能力 这些基因组特异的反义抑制剂可以阻断不同步骤的 将对病毒复制进行评估，以开发有效的 治疗指数高的多管齐下药物。这项提案有五个 具体目标：目标1-靶向引物结合位点(PBS)区域A- 病毒基因组的环区和茎环凸起结构 它们与tRNA3Lys相互作用，从而抑制逆转录； 目标2-以LtR的重复区域(R)和At位点为目标 防止链转移的HIV基因组5‘和3’LTR 前病毒基因组的反应和整合；目标3-靶向 病毒RNA基因组的TAR区域，以防止其与 调节反式激活TAT蛋白；目标4-开发一种有效的 用于有前景的反义PNA的生物递送系统；和目标5-评价 铅PNA的体外抗病毒效果及细胞毒性研究 感染HIV-1的MT-2细胞培养物中的化合物。

DESCRIPTION: (Adapted from Applicant's Abstract) The major thrust of this application continues to aim at targeting invariant non-translated domains at the 5'-end of the HIV genome with specifically designed polyamide nucleic acids (PNAs) and their derivatives. The ability of these genome specific antisense inhibitors to block various steps of viral replication will be assessed in order to develop effective multiprong drugs of high therapeutic index. The proposal has five specific aims: Aim 1- To target the primer binding site (PBS) region A- loop region and the stem-loop bulge structure of the viral genome, block their interaction with tRNA3Lys and thus inhibit reverse transcription; Aim 2 - To target the repeat region (R) of the LTR and the att site on the 5' and 3' LTR of the HIV genome to prevent the strand transfer reaction and integration of the proviral genome; Aim 3 - To target the TAR region of the viral RNA genome to prevent its interaction with regulatory transactivating Tat protein; Aim 4 - To develop an effective biodelivery system for promising antisense PNAs; and Aim 5 - To evaluate the in vitro anti viral efficacy and cytotoxicity of the lead PNA compounds in MT-2 cell cultures infected with HIV-1.