Anti-HIV-1 Composite Cellulose Acetate Phthalate Film

抗HIV-1复合醋酸纤维素邻苯二甲酸酯薄膜

• 批准号: 6803829
• 负责人: A ROBERT ROBERT NEURATH
• 金额: $ 123.24万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803829
• 关键词: antiAIDS agent; clinical research; cooperative study; drug design /synthesis /production; human subject; molecular film; patient oriented research; phthalates; topical drug application

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.

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.微粉帽是唯一可从生理流体吸附的HIV-1的候选局部杀菌剂，可防止病毒与靶CEIL接触。 HIV-1与微粉化帽之间的相互作用导致病毒崩解和包膜糖蛋白的脱落，从而导致感染性丧失。 CAP还a）灭活疱疹病毒HSV-1，HSV-2，巨细胞病毒，淋病奈瑟氏菌，阴道毛毛虫，Ducreyi，嗜血杆菌，沙丘炎，毛状腺肿瘤，毛促性虫，毛果素和细菌与细菌相关； 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具有组合微生物的所需特性。 CAP拥有既定的安全记录，大量可用，价格便宜。为了进一步利用这些属性，有必要开发一个简单，廉价，可容纳大规模生产的相应交付系统，并且最少的处置问题。这些要求是通过在水中换成含有微粉瓶盖的凝胶的情况下可分散的帽膜可转换的。需要进一步的工作来优化电影并将其带入大规模的工业生产。这将在本提案的框架内完成。瓶盖膜也适用于除CAP以外的其他微生物。为此，为此目的选择了羟丙基-Beta-Cyclodextrin（HP-BETA-CD）锌指抑制剂（ZnFI）和逆转录酶抑制剂UC781。他们将扩大HIV-1抑制的靶标。该提案的目的将在所有三个项目的框架内完成：l）预防原发性HIV-1分离株和在体外和人类宫颈组织模型中通过CAP/HP-BETA-CD/ZNFI/UC781组合在人体宫颈组织模型中进行感染； ii）a）评估帽膜，Znfi和UC781组合膜的安全性以及 - 在猴子中使用阴道后， - 微糖剂分布和b）评估帽膜和组合膜与致病性X4和R5 Simian/Human Chimeric Hiv-1病毒（SHIV）的感染的功效（SHIV）； iii）试验临床试验通过与上述项目和技术与监管核心的迭代合作，将确保建立大规模商业生产的先决条件，以有效的基于CAP的薄膜薄膜。