IDENTIFICATION AND PRECLINICAL TESTING OF MICROBICIDES FOR HPV

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 生殖道人类乳头瘤病毒(HPV)是最常见的性传播病原体，也是宫颈癌的主要原因。R21/R33联合拨款申请的目标是筛选可以抑制HPV感染的小分子，以改进的有效性识别相关化合物，并在HPV感染的临床前模型中测试最有希望的化合物的有效性。在R21阶段，完成了用于鉴定候选HPV特异性杀菌剂的高通量筛选。我们筛选了一个包含450万个小分子的数据库，寻找那些与R21相筛选中确定的结构相似的小分子，并确定了十种最佳的候选杀微生物剂。我们现在准备开始这项建议的R33阶段，基于监测雌性恒河猴生殖道中的恒河猴乳头瘤病毒(RhPV1)感染，对非人类灵长类动物的肛门HPV感染模型进行研究。在这项拨款申请中提出的研究的可行性取决于我们最近开发了一种强大而简便的新技术来高产生产传染性乳头瘤病毒。这一突破提供了足够数量的乳头瘤病毒，使人们能够筛选杀菌剂，并开发基于RhPV1的非人类灵长类动物模型，用于生殖道乳头瘤病毒感染。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Anogenital Human Papillomaviruses (HPVs) are the most common sexually transmitted pathogen and the primary cause of cervical cancer. The goal of this combined R21/R33 grant application is to screen for small molecules that can inhibit HPV infection, to identify related compounds with improved effectiveness, and to test the effectiveness of the most promising compound in a preclinical model for HPV infection. In the R21 Phase, a high throughput screen to identify candidate HPV-specific microbicides was accomplished. We screened a database of 4.5 million small molecules for ones with similar structures to those identified in the R21-phase screen and have identified the ten best candidate microbicides . We are now ready to start the R33 phase of this proposal with studies in a nonhuman primate model for anogenital HPV infection, based upon monitoring infection by Rhesus papillomavirus (RhPV1) in the reproductive tract of female Rhesus macaques. The feasibility of the studies proposed in this grant application rest upon our recently having developed a powerful and facile new technique for high yield production of infectious papillomaviruses. This breakthrough provides sufficient amounts of papillomavirus to allow one to screen for microbicides as well as to develop the RhPV1-based nonhuman primate model for anogenital papillomavirus infections.