TOPICAL PROTEGRINS TO PREVENT SEXUALLY TRANSMITTED DISEASES AND HIV INFECTION

感染人类免疫缺陷病毒(HIV)的人会患上严重的 传染性免疫缺陷的形式。免疫缺陷会导致 机会性感染和恶性肿瘤。有超过75万人 美国人感染艾滋病毒和死于艾滋病毒感染的人数较多 95%的艾滋病毒感染者。当前选择的治疗方案 病毒耐药性限制了当前药物的临床疗效。AS 然而，没有任何治疗干预可以导致消除这种情况。 感染艾滋病毒的可能性。因此，艾滋病毒感染是无法治愈的。 预防感染仍然是一项主要的公共卫生目标。干预 为人们提供更高水平的安全的努力 与高危人群发生性关系在很大程度上 降低艾滋病毒在美国的新传播率。 前列环素是一种独特的新型小肽抗生素，具有 抗逆转录病毒活性。它们对蛋白水解性切割很稳定， 化学变性，免疫原性差，被靶子迅速吸收 细胞。当浓度为5毫克/毫升时，天然和合成的前列环素完全被抑制 人类首次临床分离株(JR-CSF)的新发HIV感染 外周血淋巴母细胞培养。类似的影响也出现在 用JR-FL进行单核细胞培养。如果添加前列环素则可抑制感染 在接种之前和最多两个小时后。如果没有任何影响， 24小时后添加。有显著的结构/活动特征，如 截短版本的前列环素和相关的多肽抗生素 减少的或无效的。 此应用程序建议显著扩展我们对 前列环素作为抗HIV预防和治疗药物的生物学。我们 将评估一系列前列环素衍生品，以优化 这些代理的活动。我们将调查他们与其他人的活动 并将描绘结构/活性的性质 两性关系。最后，我们将确定HIV复制中的哪个位置 整合蛋白发挥作用并开发高容量筛查分析用于 鉴定更新、更有效的衍生肽和多肽模拟物。 最终目标是开发前列环素作为预防高血压的药物。 在性交期间使用和作为潜在的艾滋病毒传播 为那些已经感染艾滋病毒的人提供治疗剂。

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.