Anti-HIV-1 Composite Cellulose Acetate Phthalate Film

描述(由申请人提供)：醋酸酯纤维素(CAP)，用于制药工业的片剂和胶囊的肠溶膜包衣，是一种HIV-1进入抑制剂，阻断病毒上的CXCR4/CCR5共受体结合部位，并引发病毒包膜上的“末端”gp41六螺旋束。微粉化的CAP是唯一的候选局部杀菌剂，具有从生理液体中吸附HIV-1的能力，防止病毒与目标细胞接触。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，从而丧失感染性。CAP还可灭活疱疹病毒HSV-1、HSV-2、巨细胞病毒、淋球菌、阴道毛滴虫、杜热氏嗜血杆菌、沙眼衣原体、梅毒螺旋体和细菌性阴道病相关细菌；b)分别保护小鼠和恒河猴免受HSV-2和SIV的阴道感染。因此，CAP具有复配杀菌剂所需的性质。CAP有既定的安全记录，可以大量购买，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、易于大规模生产、处理问题最少的相称递送系统。满足这些要求的是一种可分散的CAP膜，可在水存在下转化为含有微粉化CAP的凝胶。还需要进一步的工作来优化薄膜并将其投入大规模工业生产。这将在这项提案的框架内完成。除CAP外，CAP膜还适用于输送杀菌剂。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。他们将扩大抑制HIV-1的目标。这项建议的目标将在以下三个项目的框架内实现：L)通过CAP/HP-β-CD/ZnFI/UC781组合在体外和在人宫颈组织模型中预防HIV-1的初级分离株和不同分支的感染；ii)评估CAP膜和ZnFI和UC781组合膜的安全性，以及--在猴子阴道应用后的杀菌剂分布；以及b)评估CAP膜和组合膜对致病X4和R5猴/人嵌合HIV-1病毒(SHV)感染的疗效；三)试点临床试验，通过与上述项目和技术与监管核心的反复协作，将确保建立大规模商业化生产有效的基于CAP的杀微生物膜的先决条件。

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.