Anti-HIV-1 Composite Cellulose Acetate Phthalate Film

描述（由申请人提供）：醋酸邻苯二甲酸纤维素（CAP），用于制药工业的片剂和胶囊的肠膜涂层，是一种HIV-1进入抑制剂，阻断病毒上的CXCR4/CCR5共受体结合位点，并在病毒包膜上引发“死端”gp41六螺旋束。微粉化的CAP是唯一一种能够吸附生理体液中的HIV-1，防止病毒与靶细胞接触的外用杀菌剂。HIV-1与微粉化的CAP相互作用导致病毒解体和包膜糖蛋白脱落，导致感染性丧失。CAP还a)灭活疱疹病毒HSV-1、HSV-2、巨细胞病毒、淋病奈瑟菌、阴道毛滴虫、杜氏嗜血杆菌、沙眼衣原体、梅毒螺旋体和与细菌性阴道病相关的细菌；b)分别保护小鼠和恒河猴免受HSV-2和SIV阴道感染。因此，CAP具有组合杀菌剂所需的性能。CAP有良好的安全记录，可以大量广泛使用，而且价格低廉。为了进一步利用这些特性，有必要开发一种简单、廉价、适合大规模生产、处置问题最少的相应的输送系统。这些要求可以通过一种可分散的CAP薄膜来满足，该薄膜在水的存在下可转化为含有微化CAP的凝胶。需要进一步的工作来优化薄膜并将其投入大规模的工业生产。这将在本建议的框架内完成。CAP薄膜也适用于递送除CAP以外的杀菌剂。为此选择了羟丙基- β -环糊精（hp - β - cd）锌指抑制剂（ZnFI）和逆转录酶抑制剂UC781。它们将扩大HIV-1抑制的靶标。该提案的目标将在所有三个项目的框架内完成：1)通过CAP/ hp - β - CD/ZnFI/UC781组合在体外和人宫颈组织模型中预防原代HIV-1分离株和不同分支的感染；II) a)评价CAP膜和ZnFI、UC781联合膜在猴子阴道应用后的安全性和杀菌剂分布；b)评价CAP膜和联合膜对致病性X4和R5猴/人嵌合HIV-1病毒（SHIV）感染的效果；III)试点临床试验，通过与上述项目和技术与监管核心的反复合作，将确保为大规模商业化生产有效的基于cap的杀微生物膜建立先决条件。

DESCRIPTION (provided by applicant): Cellulose acetate phthalate (CAP), used in the pharmaceutical industry for enteric film coating of tablets and capsules, is an HIV-1 entry inhibitor blocking the CXCR4/CCR5 coreceptor binding sites on the virus and eliciting "dead-end" gp41 six-helix bundles on the virus envelope. Micronized CAP is the only candidate topical microbicide with the capacity to adsorb from physiological fluids HIV-1, preventing virus contact with target ceils. The interaction between HIV-1 and micronized CAP leads to virus disintegration and shedding of envelope glycoproteins, resulting in loss of infectivity. CAP also a) inactivates herpesviruses HSV-1, HSV-2, cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi, Chlamydia trachomatis, Treponema pallidum and bacteria associated with bacterial vaginosis; b) protects mice and rhesus monkeys against vaginal infection by HSV-2 and SIV, respectively. Thus, CAP has the desired properties of combination microbicides. CAP has an established safety record, is widely available in large quantities and is inexpensive. To take further advantages of these properties, it is necessary to develop a commensurate delivery system which is simple, inexpensive, amenable to mass production, with a minimum of disposal problems. These requirements are met by a dispersible CAP film convertible in the presence of water into a gel containing micronized CAP. Further work is needed to optimize the film and bring it into large-scale industrial production. This will be accomplished within the framework of this proposal. CAP films are also suited for delivery of microbicides other than CAP. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) zinc finger inhibitors (ZnFI) and the reverse transcriptase inhibitor UC781 have been selected for this purpose. They will widen the targets for HIV-1 inhibition. The aims of this proposal will be accomplished within the framework of all three projects: l) Prevention of infection by primary HIV-1 isolates and distinct clades in vitro and in human cervical tissue models by CAP/HP-beta- CD/ZnFI/UC781 combinations; II) a) Assessing the safety of CAP films and ZnFI and UC781 combination films and --microbicide distribution after vaginal application in monkeys and b) Evaluating the efficacy of the CAP film and combination films against infection with pathogenic X4 and R5 simian/human chimeric HIV-1 viruses (SHIV); III) Pilot Clinical Trials, which by iterative collaboration with the above projects and the Technology & Regulatory Core, will assure the establishment of prerequisites for large-scale commercial production of efficacious CAP-based microbicidal films.