TOPICAL PROTEGRINS TO PREVENT SEXUALLY TRANSMITTED DISEASES AND HIV INFECTION

感染人类免疫缺陷病毒（艾滋病毒）的人出现严重的 一种传染性免疫缺陷 免疫缺陷导致 机会性感染和恶性肿瘤。 有超过75万的 美国艾滋病病毒感染者和艾滋病病毒感染者死亡的发生率更高， 95%的HIV感染者 当前治疗选择用于 病毒耐药性限制了目前药物的临床疗效。 作为 然而，目前还没有治疗性干预措施可以消除 感染艾滋病病毒。 因此，艾滋病毒感染无法治愈。 预防感染仍然是一个主要的公共卫生目标。 干预 努力提高人员安全水平， 与高危人群发生性关系， 降低美国艾滋病病毒的新传播率。 Protegrins是一类独特的新型小肽抗生素， 抗逆转录病毒活性。 它们对蛋白水解裂解稳定， 化学变性，免疫原性差，并迅速被靶标吸收 细胞 在5 μ g/mL时，天然和合成的保护蛋白完全抑制 人类原发性临床分离株（JR-CSF）的新发HIV感染 外周血淋巴母细胞培养。 类似的效果也出现在 使用JR-FL进行单核细胞培养。如果加入Protegrins， 接种前和接种后两小时内。 没有观察到任何影响， 24小时后加入。 有显著的结构/活动特征， 截短形式的保护蛋白和相关肽抗生素要么具有 减少或无影响。 本申请旨在大大扩展我们对 作为抗HIV预防剂和治疗剂的protegrins的生物学。 我们 将评估一系列保护素衍生物，以优化 这些代理商的活动。 我们将调查他们的活动， 逆转录病毒，并将描述结构/活性的性质 关系。 最后，我们将确定艾滋病毒复制的位点， protegrins起作用并开发了高容量筛选测定，用于 鉴定更新和更有活性的衍生肽和肽模拟物。 最终目标是开发protegrins作为预防剂， 传播艾滋病毒时，在性交中使用，并作为一个潜在的 对已经感染艾滋病毒的人的治疗剂。

Persons infected with human immunodeficiency Virus (HIV) developed a severe form of transmissible immune deficiency. The immune defect results in opportunistic infecitons and malignancies. There are over 750,000 Americans with HIV infection and death from HIV infection occurs in greater that 95 percent of HIV infected individuals. Current treatments select for viral resistance which limits the clinical efficacy of current drugs. As yet, there is no therapeutic intervention which results in the elimination of infection by HIV. Consequently, there is not cure for HIV infection. Prevention of infection remains a major public health aim. Intervention efforts which would afford an increased level of safety for persons engaging sexual intercourse with high-risk individuals could substantially decrease the rate of new transmissions of HIV in the United States. Protegrins are a unique, new class of small peptide antibiotics with antiretroviral activity. They are stable to proteolytic cleavage and chemical denaturation, poorly immunogenic, and rapidly taken up by target cells. At 5 mug/mL, natural and synthetic protegrin completely inhibited de novo HIV infection with a primary clinical isolate (JR-CSF) in human peripheral blood lymphoblast cultures. Similar effects were seen in monocyte cultures using JR-FL. Protegrins inhibited infection if added before inoculation and up to two hours later. No effects were seen if added after 24 hours. There are significant structure/activity features as truncated versions of protegrins and related peptide antibiotics either had reduced or no effect. This application proposes to significantly expand our understanding of the biology of protegrins as anti-HIV prophylactic and therapeutic agents. We will evaluate a series of protegrin derivatives in order to optimize the activity of these agents. We will survey their activity against other retroviruses and will delineate the nature of the structure/activity relationships. Finally, we will identify the site in HIV replication where protegrins act and develop high volume screening assays to be used to identify newer and more active derivative peptides and peptidomimetics. The ultimate goal is to develop protegrins as a preventative agent for the transmission of HIV when used during intercourse and as a potential therapeutic agent for those already infected with HIV.